Over the past decade, monoclonal antibodies (mAbs) have been demonstrated to be powerful therapeutic options for hematological diseases. MAbs exert selective therapeutic effects through binding specific molecules, which can minimize the frequency and magnitude of their adverse effects. The major mechanisms of the cytotoxic activity by mAbs against hematological malignancies are complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). To enhance the ADCC activity, the defucosylated version of mAbs have been developed to enhance their binding ability to Fcgamma receptor IIIa. Antibody-drug conjugates and radiolabeled mAbs are also designed to selectively kill tumor cells. Owing to the recent innovation of mAb generation and modification techniques, we can expect more benefical mAbs with diverse functions as important therapeutic strategies.
Yasuyo Ohguchi, Masahiko Ajiro, Daisuke Ogiya, Takeshi Masuda, Yawara Kawano, Shingo Usuki, Tomoaki Koga, Shinjiro Hino, Takeshi Harada, Satoru Takahashi, Seiji Okada, ichirou Jun Yasunaga, Goro Sashida, Sumio Ohtsuki, Mitsuyoshi Nakao, Takashi Minami, Akihide Yoshimi and Hiroto Ohguchi : IL-6-driven POU2AF1 and ELL2 are key regulators of multiple myeloma-distinct transcriptional and splicing programs, Blood Advances, 10, 11, 4049-4066, 2026.
(要約)
Multiple myeloma (MM) is a plasma cell neoplasm that depends on the bone marrow (BM) microenvironment; however, the underlying mechanisms of epigenetic contribution to the pathogenesis of MM are incompletely understood. Here, we delineate epigenetically driven transcriptional and splicing regulation crucial for MM. We recharacterized the transcriptional program induced by interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway by integrating chromatin immunoprecipitation sequencing, transcriptomic analyses, and CRISPR knockout screening, identifying the B-cell lineage factors POU2AF1 and ELL2, as crucial IL-6/JAK/STAT3 targets essential for MM cell growth and survival. Genetic depletion of these factors significantly suppressed MM cell growth in vitro and in the xenograft model of IL-6 humanized mice. Mechanistically, POU2AF1 and ELL2 form an autoregulatory loop with IRF4 and establish an MM-distinct transcriptional program representing cellular immaturity. The IL-6/JAK/STAT3 pathway augments this program by upregulating and recruiting these factors to MM signature genes. Furthermore, POU2AF1 and ELL2 are essential in the regulation of IL-6-dependent alternative RNA splicing. Immunocytochemical and proteomic analyses revealed that POU2AF1 colocalizes and facilitates formation of nuclear speckles, where it interacts with trans-acting splicing factors required for MM cell growth. These findings suggest dual roles of POU2AF1 and ELL2 in coordinating transcription and RNA splicing to generate MM-associated mRNA isoforms. Finally, we showed that gapmer antisense oligonucleotides targeting POU2AF1 reduced MM cell growth in the presence of soluble BM stromal cell factors, including IL-6. Our data demonstrate that IL-6-driven B-cell lineage factors are the vulnerability of MM cells and may represent novel therapeutic targets for this incurable tumor.
Yusuke Inoue, Takeshi Harada, Asuka Oda, Natsumi Ohara, Hiromi Nakagawa, Minami Urushihara, Takayuki Nakao and Ken-ichi Matsuoka : Selection of anti-CD38 antibodies for flow cytometric detection of myeloma cells treated with daratumumab or isatuximab, International Journal of Hematology, 2026.
(キーワード)
CD38 / Daratumumab / Isatuximab / Variable heavy chain of heavy chain antibody
MIYATAKA Kosuke, KANEKO Yohsuke, Taiki Hori, Yuki Yamaguchi, Seijiro Tsuji, Tomoyo Hara, Hiroki Yamagami, Sumiko Yoshida, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Takeshi Harada, Hirokazu Miki, Shingen Nakamura, Itsuro Endo, Munehide Matsuhisa, Ken-ichi Matsuoka and Ken-ichi Aihara : Red blood cell distribution width is associated with renal tubular injury in individuals with type 2 diabetes, Journal of Diabetes Investigation, 2025.
(要約)
Red blood cell distribution width (RDW) is a parameter of erythrocyte volume heterogeneity that has been traditionally used as an indicator of anemia and other hematopoietic abnormalities. Although the RDW-coefficient of variation (RDW-CV) increases in individuals with diabetes, its clinical significance in diabetic kidney disease (DKD), including glomerular and tubular injury, is unclear. Therefore, we aimed to clarify the relationship between RDW-CV and DKD indices in individuals with type 2 diabetes. This was a multicenter, retrospective, cross-sectional study. In 490 Japanese individuals with type 2 diabetes (309 men and 181 women), multiple regression analysis was performed to examine the degree of association between DKD indices (estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (uACR), log-transformed uACR (Log-uACR), urinary liver-type fatty acid-binding protein (uL-FABP)-to-creatinine ratio (uL-FABPCR), and log-transformed uL-FABPCR (Log-uL-FABPCR)) and clinical confounding factors, including RDW-CV. No significant associations were identified between RDW-CV and eGFR, uACR, or Log-uACR in either the simple or multiple linear regression analyses. However, significant and independent positive associations between RDW-CV and both uL-FABPCR and Log-uL-FABPCR were identified in multiple regression analyses (P = 0.002 and P = 0.034, respectively). Additionally, logistic regression analysis showed that RDW-CV was an aggravating factor for the incidence of advanced tubular injury [odds ratio, 1.241 (95% confidence interval: 1.010-1.520), P = 0.037]. RDW-CV was independently and positively correlated with urinary excretion of L-FABP. Therefore, RDW-CV may be a simple and useful biomarker for detecting renal tubular injury in individuals with type 2 diabetes.
(キーワード)
Red blood cell distribution width / Renal tubular injury / Type 2 diabetes
Endothelial dysfunction contributes to the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD). Pemafibrate has been shown to ameliorate MASLD in basic and clinical studies, but it is unclear whether it is also effective in the status of endothelial dysfunction. An MASLD animal model was induced in male wild-type (WT) and endothelial nitric oxide synthase (eNOS)-deficient (eNOSKO) mice by feeding them a high-fat/cholesterol/cholate diet, and they were administered either a vehicle or pemafibrate at 0.17 mg/kg/day for 10 weeks. Although pemafibrate treatment did not change plasma lipid profiles in either WT or eNOSKO mice, pemafibrate reduced plasma AST levels in both WT and eNOSKO mice compared to the levels in the vehicle-treated mice. Histopathological analysis of the liver showed that MASLD was improved in the pemafibrate-treated groups in both WT and eNOSKO mice. Compared to vehicle treatment, pemafibrate treatment significantly reduced the expression levels of hepatic NADPH oxidase subunit genes, M1 macrophages, inflammatory-cytokine-related genes and profibrotic genes in both WT and eNOSKO mice, along with reduction in hepatic oxidative stress assessed by dihydroethidium staining and 4-hydroxynonenal protein levels. Thus, pemafibrate ameliorated MASLD with reduction in oxidative stress and inflammation even in vascular endothelial dysfunction.
Yousuke Kaneko, Yutaka Kawano, Saki Kawata, Kensuke Mori, Minae Hosoki, Taiki Hori, Kohsuke Miyataka, Seijiro Tsuji, Tomoyo Hara, Hiroki Yamagami, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Takeshi Harada, Hirokazu Miki, Shingen Nakamura, Itsuro Endo, Munehide Matsuhisa, Ken-ichi Matsuoka and Ken-ichi Aihara : Mean Corpuscular Volume Is Correlated with Liver Fibrosis Defined by Noninvasive Blood Biochemical Indices in Individuals with Metabolic Disorders Aged 60 Years or Older., Journal of Clinical Medicine, 14, 13, 4680, 2025.
(要約)
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) causes progressive liver fibrosis. Although erythrocyte mean corpuscular volume (MCV) has been shown to have a positive correlation with all-cause mortality, the association between MCV and the development of MASLD has not been fully elucidated. Here, we examined the clinical significance of the association between MCV and MASLD. Methods: A cross-sectional study was carried out in 1009 Japanese individuals (including 186 individuals aged < 60 years and 823 individuals aged 60 years) with metabolic disorders. The relationships between MCV and noninvasive clinical markers of liver fibrosis, including fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS), were statistically evaluated. Results: Using multiple and logistic regression analyses in overall subjects, it was found that MCV was positively and independently associated with the values of FIB-4 index, APRI, NFS, and the prevalence of liver fibrosis defined by each index. However, the associations between the MCV value and MASLD indices were found to be positive in subjects aged 60 years but not in those aged < 60 years. Conclusions: MCV might be a simple and useful biomarker for the development of MASLD in the elderly.
Shin Kondo, Tatsuro Inoue, Takashi Saito, Yuka Kawamura, Ayane Katayama, Masafumi Nakamura, Ryohei Sumitani, Mamiko Takahashi, Masahiro Oura, Kimiko Sogabe, Takeshi Harada, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Nori Sato, Rei Ono, Masahiro Abe and Shinsuke Katoh : Allogeneic haematopoietic stem cell transplantation and patient falls: impact of lower extremity muscle strength, BMJ Supportive & Palliative Care, 15, 3, 379-386, 2025.
(要約)
Patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) have a higher risk of falls than those receiving other therapies for haematological disorders. This study aimed to investigate the impact of pretransplant lower extremity muscle strength (LEMS) on post-transplant falls. In this retrospective cohort study, patients aged ≥18 years who underwent allo-HSCT were included. All data were extracted from medical records. LEMS was defined as the knee extension force measured by a handheld dynamometer divided by the patient's weight. The receiver operating characteristic (ROC) curve was used to calculate the optimal LEMS cut-off value for prediction of falls. Patients were categorised into low and normal LEMS groups based on the cut-off value. The impact of pretransplant LEMS on post-transplant falls was analysed using a Cox proportional hazards model. In total, 101 patients were analysed. During the observation period, falls occurred in 32 patients (31.7%). The ROC curve analysis results showed that the optimal LEMS cut-off value for prediction of falls was 45.4% per body weight. In multivariate analysis, pretransplant low LEMS was a significant predictor of falls in model 1 with patient characteristics as a confounding factor and model 2 with medications-inducing falls as a confounding factor, respectively (model 1: HR 3.23, 95% CI 1.37 to 7.64; model 2: HR 2.82, 95% CI 1.20 to 6.59). Pretransplant LEMS was a significant predictor of post-transplant falls. The results of this study may help to prevent falls in patients undergoing allo-HSCT.
(キーワード)
Haematological disease / Hospital care / Leukaemia / Lymphoma / Rehabilitation / Supportive care
Kazuko Akashi, Yoshie Imai, Shingen Nakamura, Yusaku Maeda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiroh Fujii, Takeshi Harada and Hirokazu Miki : Preparedness for the future in patients with relapsed or refractory hematopoietic malignancies in the treatment process: a qualitative study, Annals of Palliative Medicine, 14, 1, 43-56, 2025.
(要約)
This study aims to clarify how patients with relapsed or refractory (R/R) hematological malignancies prepare for the future and set treatment goals. R/R hematological malignancies often require intensive therapies, including stem cell transplantation and CAR-T cell therapy, which pose high risks of adverse events. Many patients continue aggressive treatment until the end of life for pain relief or even a potential cure, despite the significant symptom burden. Understanding each patient's treatment motivations and preferences is essential to aligning care with their individual values. By examining their experiences, current health status, and treatment goals, this study seeks to provide a basis for holding early discussions on future care, contributing to individualized decision-making support for patients facing limited treatment options and uncertain prognoses. A qualitative descriptive study design was used to conduct semi-structured interviews with 16 patients with relapsed/refractory hematopoietic malignancies who were hospitalized for chemotherapy. The four main themes expressed by the participants were (I) I want to live through the treatment until the end of my life because I know recovery is difficult; (II) my current treatment depends on how much my body can endure; (III) I want to keep trying, but I am at the limit of what I can do now; and (IV) I want to continue even if the treatment is limited because I think it will help someone else. Patients with hematopoietic malignancies who are undergoing treatment may be motivated by a variety of different factors to continue with treatment. Discussing patients' goals and wishes with respect to treatment is critically important to ensure that such treatment is aligned with patients' preferences.
(キーワード)
Hematopoietic malignancy / relapsed or refractory hematopoietic malignancy (R/R hematopoietic malignancy); / patient preference / preparedness for the future / patient goals
Yusuke Inoue, Hirofumi Tenshin, Jumpei Teramachi, Ryohei Sumitani, Asuka Oda, Yusaku Maeda, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, Mamiko Takahashi, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Tomoyo Hara, Itsuro Endo, Kumiko Kagawa, Shuji Ozaki, Masahiro Hiasa, Takeshi Harada and Masahiro Abe : Elotuzumab-mediated ADCC with Th1-like Vγ9Vδ2 T cells to disrupt myeloma-osteoclast interaction, Cancer Science, 116, 2, 559-563, 2024.
(要約)
Multiple myeloma (MM) cells and osteoclasts (OCs) activate with each other to cause drug resistance. Human Th1-like Vγ9Vδ2 (γδ) T cells, important effectors against tumors, can be expanded and activated ex vivo by the aminobisphosphonate zoledronic acid in combination with IL-2. We previously reported that the expanded γδ T cells effectively targeted and killed OCs as well as MM cells. Because the expanded γδ T cells expressed CD16 on their surface, we investigated the utilization of the expanded γδ T cells for antibody-dependent cellular cytotoxicity (ADCC). Although the expanded γδ T cells alone induced cell death in MM cell lines, the addition of the anti-SLAMF7 monoclonal antibody elotuzumab (ELO) further enhanced their cytotoxic activity only against SLAMF7-expressing MM cell lines and primary MM cells. Intriguingly, ELO was also able to enhance γδ T cell-induced cell death against OCs cultured alone, and against both MM cells and OCs in their coculture settings. SLAMF7 was found to be highly expressed in OCs differentiated in vitro from monocytes by receptor activator of nuclear factor-κ B ligand and M-CSF, although monocytes only marginally expressed SLAMF7. These results demonstrate that SLAMF7 is highly expressed in both MM cells and OCs, and that the ex vivo-expanded γδ T cells can exert ELO-mediated ADCC against SLAMF7-expressing MM cells and OCs besides their direct cytotoxic activity. Further study is warranted for the innovative utilization of γδ T cells.
Ryohei Sumitani, Kohei Higashi, Masahiro Oura, Yusaku Maeda, Hikaru Yagi, Kimiko Sogabe, Mamiko Takahashi, Takeshi Harada, Shiro Fujii, Hirokazu Miki, Masahiro Abe and Shingen Nakamura : Effective Intractable Chylous Ascites Treatment by Lymphangiography with Lipiodol in a Patient with Follicular Lymphoma, Internal Medicine, 64, 8, 1223-1228, 2024.
(要約)
A 66-year-old woman was diagnosed with stage IV follicular lymphoma with a large tumor extending from the celiac artery to pelvis. Initial chemotherapy improved her lymphoma, but caused severe chylous ascites, requiring frequent paracentesis. Lymphoscintigraphy revealed radioisotope leakage into the abdominal cavity at the level of the renal hilum, indicating lymphatic vessel perforation. Lymphangiography with Lipiodol quickly resolved the chylous ascites. This case indicates that refractory chylous ascites with shrinking retroperitoneal lymphoma may require direct intervention in lymphatic vessels, and lymphangiography with Lipiodol may be effective not only as a tool for diagnosing lymphatic leakage sites but also as a treatment for lymphatic vessel damage.
Mamiko Takahashi, Shin Kondo, Kumiko Kagawa, Masafumi Nakamura, Yusaku Maeda, Ryohei Sumitani, Hikaru Yagi, Masahiro Oura, Kimiko Sogabe, Takeshi Harada, Shiroh Fujii, Hirokazu Miki, Itsuro Endo, Masahiro Abe and Shingen Nakamura : Skeletal muscle mass during chemotherapy for haematological malignancies: a retrospective study., BMJ Supportive & Palliative Care, 14, 2, 195-199, 2024.
(要約)
This study investigated whether baseline or alteration in muscle mass affects complications during chemotherapy or overall survival (OS) in haematological malignancies. Skeletal Muscle Index (SMI) was evaluated by bioimpedance analysis before and after chemotherapy in patients with haematological malignancies, and the association between muscle mass and clinical data was retrospectively analysed. Exactly 104 patients were enrolled, with a mean age of 62.2 years. SMI was 7.85 and 6.08 in male and female patients under 65 years and 7.10 and 5.92 over 65 years, before chemotherapy, respectively. Lower baseline SMI was not correlated with worse OS in total patients (p=0.915). After a median measurement interval of 30 days after chemotherapy (n=67), body weight and SMI decreased by 2.73% and 2.87% (mean), respectively. The decrease in body weight correlated with the loss of trunk muscle mass (R=0.2107) but was more strongly associated with the loss of lower limbs muscle mass (R=0.3985). The muscle mass of lower limbs significantly decreased in lymphoma patients who experienced febrile neutropenia (-0.42% vs -6.04%, p=0.040). OS significantly decreased in lymphoma patients with loss of lower limbs muscle ≥2.8% (p=0.0327). Muscle loss occurred following anticancer treatments, significantly contributing to worse outcomes. Body composition assessment and relevant multimodal prevention of muscle loss may be vital for patients receiving chemotherapy for haematological malignancies.
(キーワード)
Humans / Male / Female / Retrospective Studies / Middle Aged / Hematologic Neoplasms / Muscle, Skeletal / Aged / Adult / Antineoplastic Agents / Aged, 80 and over / Body Composition / Sarcopenia
Shingen Nakamura, Keijiro Hara, Tomoko Kobayashi, Ryohei Sumitani, Masahiro Oura, Yusaku Maeda, Kimiko Sogabe, Hikaru Yagi, Mamiko Takahashi, Shiroh Fujii, Takeshi Harada, Yoshimi Bando, Masahiro Abe and Hirokazu Miki : Tl uptake and retention mimicking malignant lymphoma in a patient with human immunodeficiency virus infection., Parasitology International, 101, 102895, 2024.
(要約)
Various opportunistic infections develop during immunodeficiency due to human immunodeficiency virus (HIV) infection. The treatment options for malignant lymphoma (ML) and toxoplasmic encephalitis (TE) are completely different; therefore, their discrimination is critical. A 25-year-old female of foreign nationality had been experiencing headaches for several weeks and suddenly developed convulsions. Brain computed tomography revealed multiple intracranial lesions; therefore, the patient was referred to the neurosurgery department. Brain magnetic resonance imaging (MRI) revealed multiple masses with surrounding edema, accompanied by enhanced contrast. The largest mass (2 cm) in the left occipital lobe exhibited ringed contrast enhancement. Her blood test results showed a CD4 count of 40/μL, positive HIV Ag/Ab, HIV-RNA level of 56 × 10 copies/mL, positive anti-Toxoplasma IgG (63 IU/mL), and negative anti-Toxoplasma IgM. Tl- single photon emission computed tomography (Tl-SPECT) revealed abnormal accumulation only in the tumor in the left occipital lobe (early T/N ratio, 3.034; delayed T/N ratio, 2.738; retention index, 0.9), which was suspected to be a ML. Both tumors, with or without high accumulation of Tl, were subjected to craniotomy biopsy. Pathological examination revealed infiltration of small lymphocytes with a necrotic background. The patient was diagnosed with TE based on a positive result of a tissue polymerase chain reaction test for Toxoplasma gondii. Two weeks after sulfamethoxazole and trimethoprim combination therapy, MRI imaging showed dramatic improvement in multiple brain tumors. This case is atypical because ML was ruled out despite high Tl-SPECT uptake and retention. Careful diagnosis through pathological examination and DNA testing is important.
Yusuke Inoue, Asuka Oda, Yusaku Maeda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, Mamiko Takahashi, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Masahiro Hiasa, Jumpei Teramachi, Takeshi Harada and Masahiro Abe : Ex vivo expansion and activation of Vγ9Vδ2 T cells by CELMoDs in combination with zoledronic acid, International Journal of Hematology, 119, 6, 626-630, 2024.
(要約)
As multiple myeloma (MM) progresses, immune effector cells decrease in number and function and become exhausted. This remains an insurmountable clinical issue that must be addressed by development of novel modalities to revitalize anti-MM immunity. Human Vγ9Vδ2 T (Vδ2+ γδ T) cells serve as the first line of defense against pathogens as well as tumors and can be expanded ex vivo from peripheral blood mononuclear cells (PBMCs) upon treatment with amino-bisphosphonates in combination with IL-2. Here, we demonstrated that next-generation immunomodulators called cereblon E3 ligase modulators (CELMoDs), as well as lenalidomide and pomalidomide, expanded Th1-like Vδ2+ γδ T cells from PBMCs in the presence of zoledronic acid (ZA). However, the expansion of Th1-like Vδ2+ γδ T cells by these immunomodulatory drugs was abolished under IL-2 blockade, although IL-2 production was induced in PBMCs. BTN3A1 triggers phosphoantigen presentation to γδ T-cell receptors and is required for γδ T-cell expansion and activation. ZA but not these immunomodulatory drugs upregulated BTN3A1 in monocytes. These results suggest that immunomodulatory drugs and ZA have cooperative roles in expansion of Th1-like Vδ2+ γδ T cells, and provide the important knowledge for clinical application of human Vδ2+ γδ T cells as effector cells.
Hiroto Ohguchi, Yasuyo Ohguchi, Sho Kubota, Kan Etoh, Ai Hamashima, Shingo Usuki, Takako Yokomizo-Nakano, Jie Bai, Takeshi Masuda, Yawara Kawano, Takeshi Harada, Mitsuyoshi Nakao, Takashi Minami, Teru Hideshima, Kimi Araki and Goro Sashida : Multiple myeloma-associated DIS3 gene is essential for hematopoiesis, but loss of DIS3 is insufficient for myelomagenesis, Blood Neoplasia, 1, 1, 2024.
Minae Hosoki, Taiki Hori, KANEKO Yohsuke, Kensuke Mori, Saya Yasui, Seijiro Tsuji, Hiroki Yamagami, Saki Kawata, Tomoyo Hara, Shiho Masuda, Yukari Mitsui, Kiyoe Kurahashi, Takeshi Harada, Shingen Nakamura, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Itsuro Endo, Munehide Matsuhisa and Ken-ichi Aihara : Causes of In-Hospital Death and Pharmaceutical Associations with Age of Death during a 10-Year Period (2011-2020) in Individuals with and without Diabetes at a Japanese Community General Hospital., Journal of Clinical Medicine, 13, 5, 1283, 2024.
(要約)
Since diabetes and its complications have been thought to exaggerate cardiorenal disease, resulting in a short lifespan, we investigated causes of death and lifespans in individuals with and without diabetes at a Japanese community general hospital during the period from 2011 to 2020. Causes of death and age of death in individuals with and those without diabetes were compared, and associations between medications used and age of death were statistically analyzed. A total of 2326 deaths were recorded during the 10-year period. There was no significant difference between the mean ages of death in individuals with and those without diabetes. Diabetic individuals had higher rates of hepato-pancreatic cancer and cardio-renal failure as causes of death. The prescription rates of antihypertensives, antiplatelets, and statins in diabetic individuals were larger than those in non-diabetic individuals. Furthermore, the use of sulfonyl urea or glinides and insulin was independently and inversely associated with the age of death. In conclusion, individuals with diabetes were treated with comprehensive pharmaceutical interventions and had life spans comparable to those of individuals without diabetes. This study's discovery of an inverse relationship between the use of insulin secretagogues or insulin and the age of death suggests that the prevention of life-threatening hypoglycemia is crucial for individuals with diabetes.
Tomoko Maruhashi, Hirokazu Miki, Kimiko Sogabe, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Takeshi Harada, Shiroh Fujii, Shingen Nakamura, Kiyoe Kurahashi, Itsuro Endo and Masahiro Abe : Acute suppression of translation by hyperthermia enhances anti-myeloma activity of carfilzomib, International Journal of Hematology, 119, 3, 291-302, 2024.
(要約)
Hyperthermia is a unique treatment option for cancers. Multiple myeloma (MM) remains incurable and innovative therapeutic options are needed. We investigated the efficacy of hyperthermia and carfilzomib in combination against MM cells. Although MM cell lines exhibited different susceptibilities to pulsatile carfilzomib treatment, mild hyperthermia at 43℃ induced MM cell death in all cell lines in a time-dependent manner. Hyperthermia and carfilzomib cooperatively induced MM cell death even under suboptimal conditions. The pro-survival mediators PIM2 and NRF2 accumulated in MM cells due to inhibition of their proteasomal degradation by carfilzomib; however, hyperthermia acutely suppressed translation in parallel with phosphorylation of eIF2α to reduce these proteins in MM cells. Recovery of β5 subunit enzymatic activity from its immediate inhibition by carfilzomib was observed at 24 h in carfilzomib-insusceptible KMS-11, OPM-2, and RPMI8226 cells, but not in carfilzomib-sensitive MM.1S cells. However, heat treatment suppressed the recovery of β5 subunit activity in these carfilzomib-insusceptible cells. Therefore, hyperthermia re-sensitized MM cells to carfilzomib. Our results support the treatment of MM with hyperthermia in combination with carfilzomib. Further research is warranted on hyperthermia for drug-resistant extramedullary plasmacytoma.
Kimiko Sogabe, Shingen Nakamura, Yoshiki Higa, Hirokazu Miki, Asuka Oda, Tomoko Maruhashi, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Masafumi Nakamura, Yusaku Maeda, Tomoyo Hara, Hiroki Yamagami, Shiroh Fujii, Kumiko Kagawa, Shuji Ozaki, Kiyoe Kurahashi, Itsuro Endo, Ken-ichi Aihara, Emiko Nakaue, Masahiro Hiasa, Jumpei Teramachi, Takeshi Harada and Masahiro Abe : Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors., International Journal of Hematology, 119, 3, 303-315, 2024.
(要約)
Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.
Masahiro Oura, Ryohei Sumitani, Yusaku Maeda, Hikaru Yagi, Mamiko Takahashi, Takeshi Harada, Shiro Fujii, Hirokazu Miki, Taiki Hori, Jumpei Murai, Kumiko Kagawa, Masahiro Abe and Shingen Nakamura : Acute myeloid leukemia developed through myeloproliferative features during immunosuppressive therapy for juvenile idiopathic arthritis, The Journal of Medical Investigation : JMI, 71, 3.4, 335-339, 2024.
(要約)
A 17-year-old male with thrombocytosis and exacerbation of arthralgia during intensified immunosuppressive therapy with tocilizumab, prednisolone, and methotrexate for juvenile idiopathic arthritis (JIA) was referred to our department. Bone marrow examination revealed myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U). Peripheral myeloblasts disappeared temporarily after discontinuation of tocilizumab but progressed to acute myeloid leukemia six months after the development of MDS/MPN-U. The patient sustained complete remission after unrelated bone marrow stem cell transplantation, followed by chemotherapy. The arthralgia also improved after chemotherapy. The possibility of developing malignancies during immunosuppressive therapy in patients with JIA should be considered. J. Med. Invest. 71 : 335-339, August, 2024.
Hiroki Yamagami, Tomoyo Hara, Saya Yasui, Minae Hosoki, Taiki Hori, Yousuke Kaneko, Yukari Mitsui, Kiyoe Kurahashi, Takeshi Harada, Sumiko Yoshida, Shingen Nakamura, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Itsuro Endo, Munehide Matsuhisa, Masahiro Abe and Ken-ichi Aihara : Cross-Sectional and Longitudinal Associations between Skin Autofluorescence and Tubular Injury Defined by Urinary Excretion of Liver-Type Fatty Acid-Binding Protein in People with Type 2 Diabetes., Biomedicines, 11, 11, 3020, 2023.
(要約)
It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury.
Saya Yasui, Yousuke Kaneko, Hiroki Yamagami, Minae Hosoki, Taiki Hori, Akihiro Tani, Tomoyo Hara, Kiyoe Kurahashi, Takeshi Harada, Shingen Nakamura, Toshiki Otoda, Tomoyuki Yuasa, Hiroyasu Mori, Akio Kuroda, Itsuro Endo, Munehide Matsuhisa, Takeshi Soeki and Ken-ichi Aihara : Dehydroepiandrosterone Sulfate, an Adrenal Androgen, Is Inversely Associated with Prevalence of Dynapenia in Male Individuals with Type 2 Diabetes., Metabolites, 13, 11, 1129, 2023.
(要約)
Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. Although skeletal muscle disorders are often found in diabetic people, the clinical significance of DHEAS in skeletal muscle remains unclear. Therefore, we aimed to determine whether DHEAS is associated with the development of skeletal muscle disorders in individuals with type 2 diabetes (T2D). A cross-sectional study was conducted in 361 individuals with T2D. Serum DHEAS levels, skeletal muscle mass index (SMI), handgrip strength (HS), and gait speed (GS) were measured in the participants. Pre-sarcopenia, sarcopenia, and dynapenia were defined according to the definitions of the AWGS 2019 criteria. DHEAS level was positively associated with HS but not with SMI or GS after adjustment of confounding factors. Multiple logistic regression analyses in total subjects showed that DHEAS level had an inverse association with the prevalence of dynapenia but not with the prevalence of pre-sarcopenia or sarcopenia. Furthermore, a significant association between DHEAS level and dynapenia was found in males but not in females. ROC curve analysis indicated that cutoff values of serum DHEAS for risk of dynapenia in males was 92.0 μg/dL. Therefore, in male individuals with T2D who have low serum levels of DHEAS, adequate exercise might be needed to prevent dynapenia.
Adult T-cell leukaemia/lymphoma (ATL) remains incurable. The NF-κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF-β-activated kinase 1 (TAK1), an IκB kinase-activating kinase, triggers the activation of NF-κB. The resorcylic acid lactone LL-Z1640-2 is a potent irreversible inhibitor of TAK1/extracellular signal-regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL-Z1640-2 against ATL. LL-Z1640-2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of strongly induced ATL cell death while downregulating MYC. LL-Z1640-2 as well as the NF-κB inhibitor BAY11-7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF-κB-IRF4-MYC axis. The treatment with LL-Z1640-2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL-Z1640-2 against IL-2-responsive ATL cells in the presence of IL-2. Therefore, LL-Z1640-2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL-Z1640-2.
Yasuyuki Omichi, Shunichi Toki, Toshihiko Nishisho, Takeshi Harada, Nori Sato and Koichi Sairyo : Atypical femoral fracture in a multiple myeloma patient undergoing treatment with denosumab: A case report and literature review, International Journal of Surgery Case Reports, 108, 2023.
Shiho Masuda, Tomoyo Hara, Hiroki Yamagami, Yukari Mitsui, Kiyoe Kurahashi, Sumiko Yoshida, Takeshi Harada, Toshiki Otoda, Tomoyuki Yuasa, Shingen Nakamura, Akio Kuroda, Itsuro Endo, Toshio Matsumoto, Munehide Matsuhisa, Masahiro Abe and Ken-ichi Aihara : Vascular Endothelial Function Is Associated with eGFR Slope in Female and Non-Smoking Male Individuals with Cardiovascular Risk Factors: A Pilot Study on the Predictive Value of FMD for Renal Prognosis., Journal of Atherosclerosis and Thrombosis, 2023.
(要約)
In individuals with cardiovascular risk factors, evaluation of vascular endothelial function enables prediction of renal prognosis in females and non-smoking males.
Emiko Nakaue, Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Takeshi Harada, Asuka Oda, Yusuke Inoue, Sou Shimizu, Yoshiki Higa, Kimiko Sogabe, Masahiro Oura, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Hiroki Yamagami, Itsuro Endo, Eiji Tanaka and Masahiro Abe : Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors., International Journal of Hematology, 2023.
(要約)
Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders.
Takeshi Harada, Hiroto Ohguchi, Asuka Oda, Michiyasu Nakao, Jumpei Teramachi, Masahiro Hiasa, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, Mamiko Takahashi, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Shuji Ozaki, Shigeki Sano, Teru Hideshima and Masahiro Abe : Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase, Blood Advances, 7, 6, 1019-1032, 2023.
(要約)
Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.
Taiki Hori, Shingen Nakamura, Hiroki Yamagami, Saya Yasui, Minae Hosoki, Tomoyo Hara, Yukari Mitsui, Shiho Masuda, Kiyoe Kurahashi, Sumiko Yoshida, Takeshi Harada, Akio Kuroda, Toshiki Otoda, Tomoyuki Yuasa, Itsuro Endo, Munehide Matsuhisa, Masahiro Abe and Ken-ichi Aihara : Phase angle and extracellular water-to-total body water ratio estimated by bioelectrical impedance analysis are associated with levels of hemoglobin and hematocrit in patients with diabetes., Heliyon, 9, 4, 2023.
(要約)
PhA and ECW/TBW but not SMI were associated with levels of Hgb and Hct in patients with diabetes. Therefore, aberrant values of PhA and ECW/TBW suggest a risk of anemia in diabetic patients.
Jumpei Teramachi, Hirokazu Miki, Shingen Nakamura, Masahiro Hiasa, Takeshi Harada and Masahiro Abe : Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents., Journal of Bone and Mineral Metabolism, 1-16, 2023.
(要約)
MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.
Yoshiki Higa, Masahiro Hiasa, Hirofumi Tenshin, Emiko Nakaue, Mariko Tanaka, SooHa Kim, Motosumi Nakagawa, Sou Shimizu, Kotaro Tanimoto, Jumpei Teramachi, Takeshi Harada, Asuka Oda, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Hiroki Yamagami, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe : The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2., Antioxidants, 12, 1, 2023.
(要約)
Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.
【Introduction】The survival rate in patients with HIV infection and acquired immunodeficiency syndrome (AIDS) has been improved dramatically due to the advances in anti-HIV drug therapy, while aging-associated complications become a critical issue. The incidence of sudden occurrence of AIDS without prior detection of HIV infection, so called ``Ikinari AIDS'', still remains high. 【Objective】We retrospectively analyzed the incidence and clinical characteristics of HIV/AIDS patients in both Tokushima University Hospital and Tokushima Prefectural Central Hospital. 【Results】Eighty four patients (74 males and 10 females) with a median age of 39 years old (range 16 - 85) were enrolled. Thirty-four patients (40.5%) were diagnosed with ``Ikinari AIDS'' from 2001 to 2020. All 4 patients were diagnosed with ``Ikinari AIDS'' after 2020. AIDS-defining illnesses were diagnosed as follows ; pneumocystis pneumonia in 21 cases, CMV infection in 8 cases and candidiasis in 6 cases. All patients over 60 years old were suffered from AIDS. Other complications included syphilis in 17 cases, hepatitis B infection in 12 and herpes zoster in 7. 【Discussion/Conclusion】In Tokushima, the incidence rate of ``Ikinari AIDS'' appeared to be higher than that of national average. COVID - 19 pandemic hampered the public health care services of awareness-raising activity for HIV infection and telephone consultations about HIV, which may become more lease asymptomatic HIV patients without diagnosis. For early diagnosis of HIV/AIDS, it is becoming more important to share information to make early screening of HIV infection among medical staffs, such as medical doctors, dentists, nurses, pharmacists and MSWs.
Sou Shimizu, Jumpei Teramachi, Takeshi Harada, Masahiro Hiasa, Hirofumi Tenshin, A Oda, A Seki, Y Inoue, Kotaro Tanimoto, Yoshiki Higa, M Oura, K Sogabe, Takeshi Harada, Ryohei Sumitani, T Maruhashi, H Yamagami, Y Sawa, Itsuro Endo, K Tsuneyama, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe : Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival, International Journal of Myeloma, 12, 2, 14-23, 2022.
(要約)
<p>The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. <i>CIP2A</i> gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.</p>
Hirofumi Tenshin, Jumpei Teramachi, Mohannad Ashtar, Masahiro Hiasa, Yusuke Inoue, Asuka Oda, Kotaro Tanimoto, Sou Shimizu, Yoshiki Higa, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Mayu Sebe, Rie Tsutsumi, Hiroshi Sakaue, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe : TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression., Clinical & translational immunology, 11, 1, 2022.
(要約)
TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA.
Masahiro Hiasa, Takeshi Harada, Eiji Tanaka and Masahiro Abe : Pathogenesis and treatment of multiple myeloma bone disease., Japanese Dental Science Review, 57, 164-173, 2021.
(要約)
Multiple myeloma (Plasma cell myeloma), a malignancy of the plasma cells, exhibits tumor expansion preferentially in the bone marrow and the development of bone-destructive lesions. Multiple myeloma is still an incurable disease with changes in the bone marrow microenvironment in favor of the survival and proliferation of multiple myeloma cells and bone destruction. In this review, we described the recent findings on the regulators involved in the development of myeloma bone diseases, and succinctly summarize currently available therapeutic options and the development of novel bone modifying agents for myeloma treatment.
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Asuka Oda, Ariunzaya Bat-Erdene, Takeshi Harada, Shingen Nakamura, Mohannad Ashtar, Sou Shimizu, Masami Iwasa, Kimiko Sogabe, Masahiro Oura, Shiroh Fujii, Kumiko Kagawa, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma, Haematologica, 106, 5, 1401-1413, 2021.
(要約)
Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.
A 33-year-old man was admitted to our hospital for fever and abdominal pain. A blood analysis revealed pancytopenia and increased serum pancreatic enzymes with disseminated intravascular coagulation. A detailed examination revealed acute pancreatitis, with diffuse swelling of the pancreas and diffuse beaded dilatation of the main pancreatic duct, which mimicked autoimmune pancreatitis complicated by acute myeloid leukemia. Systemic cytotoxic chemotherapy led to the remission of leukemia and pancreatitis. We hypothesized that the etiology of acute pancreatitis was invasion of leukemia cells. Acute pancreatitis is rare as a symptom of leukemia; however, we should consider the possibility of leukemia during the differential diagnosis of acute pancreatitis.
Teru Hideshima, Daisuke Ogiya, Jiye Liu, Takeshi Harada, Keiji Kurata, Jooeun Bae, Walter Massefski and Kenneth Anderson : Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways, Leukemia, 35, 1, 177-188, 2021.
(要約)
Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide show remarkable antitumor activity in multiple myeloma (MM) via directly inhibiting MM-cell growth in the bone marrow (BM) microenvironment and promoting immune effector cell function. They are known to bind to the ubiquitin 3 ligase CRBN complex and thereby triggering degradation of IKZF1/3. In this study, we demonstrate that IMiDs also directly bind and activate zeta-chain-associated protein kinase-70 (Zap-70) via its tyrosine residue phosphorylation in T cells. IMiDs also triggered phosphorylation of Zap-70 in natural killer (NK) cells. Importantly, increased granzyme-B (GZM-B) expression and NK-cell activity triggered by IMiDs is associated with Zap-70 activation and inhibited by Zap-70 knockdown (KD), independent of CRBN. We also demonstrate a second mechanism whereby IMiDs trigger GZM-B and NK cytotoxicity which is CRBN and IKZF3 mediated, and inhibited or enhanced by KD of CRBN or IKZF3, respectively, independent of Zap-70. Our studies therefore show that IMiDs can enhance NK and T-cell cytotoxicity in (1) ZAP-70-mediated CRBN independent, as well as (2) CRBN-mediated ZAP-70 independent mechanisms; and provide the framework for developing novel therapeutics to activate Zap-70 and thereby enhance T and NK anti-MM cytotoxicity.
Mamiko Takahashi, Ryohei Sumitani, Taiki Hori, Jumpei Murai, Shiyori Kawata, Masahiro Oura, Kimiko Sogabe, Takeshi Harada, Shiroh Fujii, Hirokazu Miki, Kumiko Kagawa, Masahiro Abe and Shingen Nakamura : Intravenous busulfan-based conditioning with autologous stem cell transplantation for refractory B-cell lymphoma with central nervous system involvement., The Journal of Medical Investigation : JMI, 68, 1.2, 196-201, 2021.
(要約)
The prognosis of relapsed or refractory lymphoma with central nervous system (CNS) involvement remains poor because of the lack of anticancer drugs with sufficient CNS penetration. [Case 1] A 65-year-old man was diagnosed with Stage IV mantle cell lymphoma. After two courses of chemotherapy and autologous hematopoietic stem cell (HSC) collection, urinary retention with fever developed. Cerebrospinal fluid analysis revealed leptomeningeal involvement, which was refractory to high-dose methotrexate therapy. Autologous peripheral blood stem cell transplantation (ASCT) was performed, followed by intravenous busulfan (ivBU), cyclophosphamide, and etoposide ; thereafter, no relapse has been detected for over six years. [Case 2] A 40-year-old woman with right lower hemiplegia was diagnosed with primary CNS lymphoma. Although four courses of high-dose methotrexate therapy were administered, the cerebral tumor increased in size. HSCs were collected after methotrexate therapy, and ASCT was performed in addition to conditioning using ivBU, cyclophosphamide, and etoposide, followed by whole-brain and local boost irradiation. She achieved complete remission, but relapsed two years after ASCT. High-dose ivBU-containing conditioning regimens with ASCT may be useful for refractory B-cell lymphoma with CNS involvement. J. Med. Invest. 68 : 196-201, February, 2021.
Mohannad Ashtar, Hirofumi Tenshin, Jumpei Teramachi, Ariunzaya Bat-Erdene, Masahiro Hiasa, Asuka Oda, Kotaro Tanimoto, Sou Shimizu, Yoshiki Higa, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Shingen Nakamura, Shiroh Fujii, Ryohei Sumitani, Hirokazu Miki, Kengo Udaka, Mamiko Takahashi, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat., Cancers, 12, 4, 2020.
(要約)
Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.
Matthew Ho, Tianzeng Chen, Jiye Liu, Paul Dowling, Teru Hideshima, Li Zhang, Eugenio Morelli, Gulden Camci-Unal, Xinchen Wu, Yu-Tzu Tai, Kenneth Wen, Mehmet Samur, Robert L. Schlossman, Ralph Mazitschek, Emma L. Kavanagh, Sinead Lindsay, Takeshi Harada, Amanda McCann, Kenneth C. Anderson, Peter O'Gorman and Giada Bianchi : Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling, Leukemia, 34, 1, 196-209, 2020.
Shuji Ozaki, Takeshi Harada, Hikaru Yagi, Etsuko Sekimoto, Hironobu Shibata, Toshio Shigekiyo, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa and Masahiro Abe : Polyclonal Immunoglobulin Recovery after Autologous Stem Cell Transplantation Is an Independent Prognostic Factor for Survival Outcome in Patients with Multiple Myeloma, Cancers, 12, 1, 12, 2019.
(要約)
We retrospectively analyzed multiple myeloma (MM) patients who underwent autologous stem cell transplantation (ASCT) without maintenance therapy to assess the impact of recovery of normal immunoglobulin (Ig) on clinical outcomes. The recovery of polyclonal Ig was defined as normalization of all values of serum IgG, IgA, and IgM 1 year after ASCT. Among 50 patients, 26 patients showed polyclonal Ig recovery; 14 patients were in ≥complete response (CR) and 12 remained in non-CR after ASCT. The patients with Ig recovery exhibited a significantly better progression-free survival (PFS, median, 46.8 vs 26.7 months, = 0.0071) and overall survival (OS, median, not reached vs 65.3 months, < 0.00001) compared with those without Ig recovery. The survival benefits of Ig recovery were similarly observed in ≥CR patients (median OS, not reached vs 80.5 months, = 0.061) and non-CR patients (median OS, not reached vs 53.2 months, = 0.00016). Multivariate analysis revealed that non-CR and not all Ig recovery were independent prognostic factors for PFS (HR, 4.284, 95%CI (1.868-9.826), = 0.00059; and HR, 2.804, 95%CI (1.334-5.896), = 0.0065, respectively) and also for OS (HR, 8.245, 95%CI (1.528-44.47), = 0.014; and HR, 36.55, 95%CI (3.942-338.8), = 0.0015, respectively). Therefore, in addition to the depth of response, the recovery of polyclonal Ig after ASCT is a useful indicator especially for long-term outcome and might be considered to prevent overtreatment with maintenance therapy in transplanted patients with MM.
Masami Iwasa, Takeshi Harada, Asuka Oda, Ariunzaya Bat-Erdene, Jumpei Teramachi, Hirofumi Tenshin, Mohannad Ashtar, Masahiro Oura, Kimiko Sogabe, Kengo Udaka, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Shuji Ozaki and Masahiro Abe : PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ., Oncotarget, 10, 20, 1903-1917, 2019.
(要約)
gene silencing abolished the PD-L1 upregulation by panobinostat and IFN-γ in combination, indicating a critical role for STAT1. These results suggest that panobinostat enhances PD-L1 expression by facilitating the IFN-γ-STAT1 pathway in a ligand-dependent manner in MM cells with ambient IFN-γ. PD-L1 upregulation should be taken into account when combining immunotherapies with panobinostat.
A 68-year-old woman presented with sustained fever for more than 1 month and admitted due to hematemesis and systemic edema. Computed tomography scan revealed swelling of the cervical, paraaortic lymph nodes. Blood test results showed severe anemia, elevation of white blood cell count, elevation of liver enzyme and coagulopathy with high C-reactive protein. Biopsy of the right cervical lymph node showed proliferation of abnormal lymphoid cells with necrosis and hemorrhage, which are positive for CD79α, CD30, MUM-1, and bcl-6 and negative for CD20, CD5, CD10, ALK, CD38, CD138, and EBER. Gene rearrangement of immunoglobulin heavy chain was detected in tumor cells. Bone marrow aspiration showed tumor involvement. The patient was diagnosed with de novo CD20-negative diffuse large B-cell lymphoma(DLBCL)stage IV B. Reduced CHOP therapy was performed under artificial respiration due to pulmonary edema and takotsubo cardiomyopathy. Although her general condition and high CRP levels temporarily improved, she died 47 days after admission due to rapid relapse. De novo CD20-negative DLBCL was rare and presented with high CRP levels and rapid progression, and was thought to be clinically different from the existing DLBCL. It is imperative to elucidate molecular pathophysiology and establish new treatment strategy for de novo CD20-negative DLBCL.
(キーワード)
CD20 / fever of unknown origin / diffuse large B-cell lymphoma / CRP
Anamaria Gulla, Teru Hideshima, Giada Bianchi, MT Fulciniti, M Samur Kemal, J Qi, Yu-Tzu Tai, Takeshi Harada, E Morelli, N Amodio, R Carrasco, P Tagliaferri, NC Munshi, P Tassone and C. Kenneth Anderson : Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma, Leukemia, 32, 4, 996-1002, 2018.
(要約)
Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression-free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-κB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-κB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.
Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.
A 64-year-old woman presented with lower leg edema, fever, and bilateral joint pain, involving the wrists, fingers, and knees, in April 201X. Serological test results were negative for rheumatoid factor, antinuclear antibody, and anti-cyclic citrullinated peptide antibody. A diagnosis of remitting seronegative symmetrical synovitis with pitting edema syndrome, a type of seronegative rheumatoid arthritis, was made and prednisolone was administered. The joint pain was refractory to prednisolone therapy. In February, 201X+2, the patient presented with right cervical lymphadenopathy. The CT scan revealed swelling of the cervical, axillary, and inguinal lymph nodes bilaterally and rapidly enlarged. In April, 18F-fluorodeoxyglucose PET/CT scan showed an abnormal collection in the enlarged lymph nodes. The patient subsequently developed hoarseness with dyspnea and attended our department. Blood test results showed high levels of lactate dehydrogenase (547U/L) and soluble interleukin‐2 receptor (34200 IU/L) and were positive for anti-human T-cell leukemia virus type1 (HTLV‐1) antibody. Biopsy of the right cervical lymph node showed proliferation of abnormal lymphoid cells positive for CD3, CD4, and CD25 and negative for CD7. Monoclonal integration of HTLV‐1 proviral DNA was detected in the lymph node. A diagnosis of adult T-cell leukemia/lymphoma (ATLL), lymphoma type was made. The pain involving multiple joints was attributed to HTLV‐1associated arthropathy. Immunosuppressive therapy for HTLV‐1 carrier status may have played a role in the development of ATLL.
Hiroto Ohguchi, Takeshi Harada, Morihiko Sagawa, Shohei Kikuchi, YT Tai, PG Richardson, Teru Hideshima and KC Anderson : KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival, Leukemia, 31, 12, 2661-2669, 2017.
(要約)
Recent studies have delineated cancer-type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in multiple myeloma (MM) cells; and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6B abrogate MM cell growth and survival. Tumor necrosis factor-α or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting that KDM6B is regulated by NF-κB signaling in MM cells. RNA-seq and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1 and FOS, and upregulates expression of these genes without affecting H3K27 methylation level. Overexpression of catalytically inactive KDM6B activates expression of MAPK pathway-related genes, confirming its function independent of demethylase activity. We further demonstrate that downstream targets of KDM6B, ELK1 and FOS, confer MM cell growth. Our study therefore delineates KDM6B function that links NF-κB and MAPK signaling pathway mediating MM cell growth and survival, and validates KDM6B as a novel therapeutic target in MM.
Takeshi Harada, Ohguchi Hiroto, Grondin Yohann, Kikuchi Shohei, Sagawa Morihiko, Tai Yu-Tzu, Mazitschek Ralph, Hideshima Teru and Anderson C. Kenneth : HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications, Leukemia, 31, 12, 2670-2677, 2017.
(要約)
Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.
Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated "side population" fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor -activated kinase-1 (TAK1), and thus activated NF-B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-B activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.
Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, K. Mehmet Samur, Yu-Tzu Tai, C. Nikhil Munshi, Masahiro Kizaki, Teru Hideshima and C. Kenneth Anderson : Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) as a Novel Therapeutic Target in Multiple Myeloma, Clinical Cancer Research, 23, 17, 5225-5237, 2017.
(要約)
To investigate the biological and clinical significance of ribonucleotide reductase (RR) in multiple myeloma. We assessed the impact of RR expression on patient outcome in multiple myeloma. We then characterized the effect of genetic and pharmacologic inhibition of ribonucleotide reductase catalytic subunit M1 (RRM1) on multiple myeloma growth and survival using siRNA and clofarabine, respectively, in both and mouse xenograft models. Newly diagnosed multiple myeloma patients with higher RRM1 expression have shortened survival. Knockdown of RRM1 triggered significant growth inhibition and apoptosis in multiple myeloma cells, even in the context of the bone marrow microenvironment. Gene expression profiling showed upregulation of DNA damage response genes and p53-regulated genes after RRM1 knockdown. Immunoblot and qRT-PCR analysis confirmed that γ-H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, and BRCA2 were upregulated/activated. Moreover, immunoblots showed that p53, p21, Noxa, and Puma were activated in p53 wild-type multiple myeloma cells. Clofarabine, a purine nucleoside analogue that inhibits RRM1, induced growth arrest and apoptosis in p53 wild-type cell lines. Although clofarabine did not induce cell death in p53-mutant cells, it did trigger synergistic toxicity in combination with DNA-damaging agent melphalan. Finally, we demonstrated that tumor growth of RRM1-knockdown multiple myeloma cells was significantly reduced in a murine human multiple myeloma cell xenograft model. Our results therefore demonstrate that RRM1 is a novel therapeutic target in multiple myeloma in the preclinical setting and provide the basis for clinical evaluation of RRM1 inhibitor, alone or in combination with DNA-damaging agents, to improve patient outcome in multiple myeloma. .
Ariunzaya Bat-Erdene, Hirokazu Miki, Asuko Oda, Shingen Nakamura, Jumpei Teramachi, Ryota Amachi, Hirofumi Tenshin, Masahiro Hiasa, Masami Iwasa, Takeshi Harada, Shiroh Fujii, Kimiko Sogabe, Kumiko Kagawa, Sumiko Yoshida, Itsuro Endo, Ken-ichi Aihara and Masahiro Abe : Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors., Oncotarget, 7, 48, 79064-79075, 2016.
(要約)
Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.
Jana Jakubikova, Danka Cholujova, Teru Hideshima, Paulina Gronesova, Andrea Soltysova, Takeshi Harada, Jungnam Joo, Sun-Young Kong, Raphael E. Szalat, Paul G. Richardson, Nikhil C. Munshi, David M. Dorfman and Kenneth C. Anderson : A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications, Oncotarget, 7, 47, 77326-77341, 2016.
(要約)
Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM.
Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.
Rikio Suzuki, Shohei Kikuchi, Takeshi Harada, Naoya Mimura, Jiro Minami, Hiroto Ohguchi, Yasuhiro Yoshida, Morihiko Sagawa, Gullu Gorgun, Diana Cirstea, Francesca Cottini, Jana Jakubikova, Tzu Yu Tai, Dharminder Chauhan, G. Paul Richardson, Nikhil Munshi, Kiyoshi Ando, Teruhiro Utsugi, Teru Hideshima and C. Kenneth Anderson : Combination of a selective HSP90α/β inhibitor and a RAS-RAF-MEK-ERK signaling pathway inhibitor triggers synergistic cytotoxicity in multiple myeloma cells, PLoS ONE, 10, 12, e0143847, 2015.
(要約)
Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.
James Derek Hanson, Shingen Nakamura, Ryota Amachi, Masahiro Hiasa, Asuka Oda, Daisuke Tsuji, Kohji Itoh, Takeshi Harada, Kazuki Horikawa, Jumpei Teramachi, Hirokazu Miki, Toshio Matsumoto and Masahiro Abe : Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation, Oncotarget, 6, 32, 33568-33586, 2015.
(要約)
Cancer cells robustly expel lactate produced through enhanced glycolysis via monocarboxylate transporters (MCTs) and maintain alkaline intracellular pH. To develop a novel therapeutic strategy against multiple myeloma (MM), which still remains incurable, we explored the impact of perturbing a metabolism via inhibiting MCTs. All MM cells tested constitutively expressed MCT1 and MCT4, and most expressed MCT2. Lactate export was substantially suppressed to induce death along with lowering intracellular pH in MM cells by blockade of all three MCT molecules with α-cyano-4-hydroxy cinnamate (CHC) or the MCT1 and MCT2 inhibitor AR-C155858 in combination with MCT4 knockdown, although only partially by knockdown of each MCT. CHC lowered intracellular pH and severely curtailed lactate secretion even when combined with metformin, which further lowered intracellular pH and enhanced cytotoxicity. Interestingly, an ambient acidic pH markedly enhanced CHC-mediated cytotoxicity, suggesting preferential targeting of MM cells in acidic MM bone lesions. Furthermore, treatment with CHC suppressed hexokinase II expression and ATP production to reduce side populations and colony formation. Finally, CHC caused downregulation of homing receptor CXCR4 and abrogated SDF-1-induced migration. Targeting tumor metabolism by MCT blockade therefore may become an effective therapeutic option for drug-resistant MM cells with elevated glycolysis.
Güllü Görgün, K. Mehmet Samur, B. Kristen Cowens, Steven Paula, Giada Bianchi, E. Julie Anderson, E. Randie White, Ahaana Singh, Hiroto Ohguchi, Rikio Suzuki, Shohei Kikuchi, Takeshi Harada, Teru Hideshima, Tzu Yu Tai, P. Jacob Laubach, Noopur Raje, Florence Magrangeas, Stephane Minvielle, Herve Avet-Loiseau, C. Nikhil Munshi, M. David Dorfman, G. Paul Richardson and C. Kenneth Anderson : Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma, Clinical Cancer Research, 21, 20, 4617-4618, 2015.
(要約)
PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu. Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138(+) multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti-multiple myeloma immune response and tumor cell growth. Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression. Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy.
S. Kikuchi, R. Suzuki, H. Ohguchi, Y. Yoshida, D. Lu, F. Cottini, J. Jakubikova, G. Bianchi, Takeshi Harada, G. Gorgun, T. Y. Tai, G. P. Richardson, T. Hideshima and C. K. Anderson : Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma, Leukemia, 29, 9, 1918-1927, 2015.
(要約)
Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM.
M. Hiasa, J. Teramachi, A. Oda, R. Amachi, Takeshi Harada, S. Nakamura, H. Miki, S. Fujii, K. Kagawa, K. Watanabe, I. Endo, Y. Kuroda, T. Yoneda, D. Tsuji, M. Nakao, E. Tanaka, K. Hamada, S. Sano, K. Itoh, T. Matsumoto and M. Abe : Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma, Leukemia, 29, 1, 207-217, 2014.
(要約)
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.
(キーワード)
Base Sequence / Bone Morphogenetic Protein 2 / Cell Differentiation / Cell Line, Tumor / DNA Primers / Disease Progression / Humans / Multiple Myeloma / Osteoblasts / Osteoporosis / Protein Serine-Threonine Kinases / Proto-Oncogene Proteins / Real-Time Polymerase Chain Reaction / Signal Transduction
Shuji Ozaki, Takeshi Harada, Takayuki Saitoh, Chihiro Shimazaki, Mitsuhiro Itagaki, Hideki Asaoku, Yoshiaki Kuroda, Takaaki Chou, Yumiko Yoshiki, Kenshi Suzuki, Hirokazu Murakami, Kunihiko Hayashi, Roberto Mina, Antonio Palumbo and Kazuyuki Shimizu : Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation, Acta Haematologica, 132, 2, 211-219, 2014.
(要約)
Novel agents such as thalidomide, lenalidomide and bortezomib have dramatically changed the treatment paradigm of multiple myeloma (MM). However, it is not clear whether these agents improve the prognosis of elderly patients who have undergone autologous stem cell transplantation (auto-SCT). We retrospectively analyzed the outcome of 318 newly diagnosed patients aged 65-70 years who were treated between January 1, 2004, and December 31, 2009. As initial therapy, 192 patients were treated with conventional chemotherapy,88 with novel agent-containing regimens, 21 with conventional chemotherapy plus auto-SCT and the remaining 17 with novel agents plus auto-SCT. The median progression-free survival was 19.1, 24.5, 26.8 and 35.2 months, respectively, and the 5-year overall survival (OS) was 40, 62, 63 and 87%, respectively. Initial therapy with novel agents (p < 0.001) or auto-SCT (p < 0.02) significantly improved OS compared with the group without these treatment modalities. Salvage therapy with novel agents also significantly improved survival after relapse compared with conventional chemotherapy alone (p < 0.04). In a multivariate analysis, the use of novel agents was an independent prognostic factor significantly associated with extended OS(p < 0.003). These results indicate that novel agents and auto-SCT had a major impact on OS in eligible patients in this subgroup of MM.
Takeshi Harada, Shuji Ozaki, Asuka Oda, Daisuke Tsuji, Akishige Ikegame, Masami Iwasa, Kengo Udaka, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Yoshiaki Kuroda, Shigeto Kawai, Kouji Itou, Hisafumi Yamada-Okabe, Toshio Matsumoto and Masahiro Abe : Combination with a Defucosylated Anti-HM1.24 Monoclonal Antibody plus Lenalidomide Induces Marked ADCC against Myeloma Cells and Their Progenitors, PLoS ONE, 8, 12, e83905, 2013.
(要約)
The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic "side population" in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells.
Shingen Nakamura, Hirokazu Miki, Shinsuke Kido, Ayako Nakano, Masahiro Hiasa, Asuka Oda, Hiroe Amou, Keiichiro Watanabe, Takeshi Harada, Shiro Fujii, Kyoko Takeuchi, Kumiko Kagawa, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : Activating transcription factor 4, an ER stress mediator, is required for, but excessive ER stress suppresses osteoblastogenesis by bortezomib, International Journal of Hematology, 98, 1, 66-73, 2013.
(要約)
Endoplasmic reticulum (ER) stress is induced in matrix-producing osteoblasts and plays an essential role in osteoblastogenesis. Although the bone anabolic activity of proteasome inhibitors has been demonstrated, the roles of ER stress induced by proteasome inhibition in osteoblastogenesis remain largely unknown. Here we show that bortezomib translationally increases protein levels of activating transcription factor 4 (ATF4), a downstream mediator of ER stress, in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells. The suppression of ATF4 expression by siRNA abrogated osteocalcin expression and mineralized nodule formation by MC3T3-E1 cells induced by bortezomib, indicating a critical role for ATF4 in bortezomib-mediated osteoblastogenesis. However, bortezomib at 20 nM or higher abolished the mineralized nodule formation along with reductions in the expression of osteoblastogenesis mediators β-catenin and Osterix. Furthermore, at 50 nM, bortezomib induced the expression of C/EBP homologous protein (CHOP), suggesting activation of the ATF4-CHOP pro-apoptotic pathway. These results suggest that a low dose of bortezomib induces osteogenic activity, but that, in contrast, excessive ER stress caused by bortezomib at higher doses hampers osteoblastogenesis. Therefore, dosing schedules for proteasome inhibitors warrant further study to maximize anabolic actions without compromising anti-MM activity in patients with multiple myeloma (MM).
Takeshi Harada, Shuji Ozaki, Asuka Oda, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Kyoko Takeuchi, Toshio Matsumoto and Masahiro Abe : Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma., International Journal of Hematology, 97, 6, 743-748, 2013.
(要約)
Transient inflammatory reactions have been reported in a subpopulation of patients with multiple myeloma (MM) during lenalidomide (Len) plus dexamethasone (DEX) therapy. Here, we examined serum levels of Th1 (IL-2 and IFN-) and Th2 cytokines (IL-6 and TNF-) in nine refractory or relapsed MM patients treated with Len plus low-dose DEX. Six patients showed elevation of C-reactive protein (CRP) after the initiation of therapy. In these patients, IFN- and IL-6 were also elevated in two and three patients, respectively. The remaining three patients showed no appreciable changes in CRP or these cytokines. Furthermore, Len enhanced the production of both Th1 and Th2 cytokines in normal peripheral blood mononuclear cells and in patient bone marrow mononuclear cells containing primary myeloma cells and lymphocytes. These results suggest that the modulation of the Th1 and Th2 cytokine production by Len may contribute to transient inflammatory reaction in MM patients.
A. Ikegame, S. Ozaki, D. Tsuji, Takeshi Harada, S. Fujii, S. Nakamura, H. Miki, A. Nakano, K. Kagawa, K. Takeuchi, M. Abe, K. Watanabe, M. Hiasa, N. Kimura, Y. Kikuchi, A. Sakamoto, K. Habu, M. Endo, K. Itoh, H. Yamada-Okabe and T. Matsumoto : Small molecule antibody targeting HLA class i inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors, Leukemia, 26, 9, 2124-2134, 2012.
(要約)
Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of β-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy.
(キーワード)
cancer stem cell / diabody / lipid rafts / multiple myeloma / side population
Kumiko Kagawa, Ayako Nakano, Hirokazu Miki, Asuka Oda, Hiroe Amou, Kyoko Takeuchi, Shingen Nakamura, Takeshi Harada, Shiro Fujii, Kenichiro Yata, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : Inhibition of tace activity enhances the susceptibility of myeloma cells to TRAIL, PLoS ONE, 7, 2, e31594, 2012.
(要約)
TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) selectively induces apoptosis in various cancer cells including myeloma (MM) cells. However, the susceptibility of MM cells to TRAIL is largely low in most of MM cells by yet largely unknown mechanisms. Because TNF-α converting enzyme (TACE) can cleave some TNF receptor family members, in the present study we explored the roles of proteolytic modulation by TACE in TRAIL receptor expression and TRAIL-mediated cytotoxicity in MM cells. MM cells preferentially expressed death receptor 4 (DR4) but not DR5 on their surface along with TACE. Conditioned media from RPMI8226 and U266 cells contained a soluble form of DR4. The DR4 levels in these conditioned media were reduced by TACE inhibition by the TACE inhibitor TAPI-0 as well as TACE siRNA. Conversely, the TACE inhibition restored surface levels of DR4 but not DR5 in these cells without affecting DR4 mRNA levels. The TACE inhibition was able to restore cell surface DR4 expression in MM cells even in the presence of bone marrow stromal cells or osteoclasts, and enhanced the cytotoxic effects of recombinant TRAIL and an agonistic antibody against DR4 on MM cells. These results demonstrate that MM cells post-translationally down-modulate the cell surface expression of DR4 through ectodomain shedding by endogenous TACE, and that TACE inhibition is able to restore cell surface DR4 levels and the susceptibility of MM cells to TRAIL or an agonistic antibody against DR4. Thus, TACE may protect MM cells from TRAIL-mediated death through down-modulation of cell-surface DR4. It can be envisaged that TACE inhibition augments clinical efficacy of TRAIL-based immunotherapy against MM, which eventually becomes resistant to the present therapeutic modalities.
Ayako Nakano, Hirokazu Miki, Shingen Nakamura, Takeshi Harada, Asuka Oda, Hiroe Amou, Shiro Fujii, Kumiko Kagawa, Kyoko Takeuchi, Shuji Ozaki, Toshio Matsumoto and Masahiro Abe : Up-regulation of hexokinaseII in myeloma cells: Targeting myeloma cells with 3-bromopyruvate, Journal of Bioenergetics and Biomembranes, 44, 1, 31-38, 2012.
(要約)
Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. However, HKII levels and its roles in ATP production and ATP-dependent cellular process have not been well studied in hematopoietic malignant cells including multiple myeloma (MM) cells.We demonstrate herein that HKII is constitutively over-expressed in MM cells. 3-bromopyruvate (3BrPA), an inhibitor of HKII, promptly and substantially suppresses ATP production and induces cell death in MM cells. Interestingly, cocultures with osteoclasts (OCs) but not bone marrow stromal cells (BMSCs) enhanced the phosphorylation of Akt along with an increase in HKII levels and lactate production in MM cells. The enhancement of HKII levels and lactate production in MM cells by OCs were mostly abrogated by the PI3K inhibitor LY294002, suggesting activation of glycolysis in MM cells by OCs via the PI3K-Akt-HKII pathway. Although BMSCs and OCs stimulate MM cell growth and survival, 3BrPA induces cell death in MM cells even in cocultures with OCs as well as BMSCs. Furthermore, 3BrPA was able to diminish ATP-dependent ABC transporter activity to restore drug retention in MM cells in the presence of OCs. These results may underpin possible clinical application of 3BrPA in patients with MM.
Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2), KG-1 (ABCB1) and HepG2 cells (ABCB1 and ABCG2). Interestingly, although side population (SP) cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.
Hirokazu Miki, Shuji Ozaki, Shingen Nakamura, Asuka Oda, Hiroe Amou, Akishige Ikegame, Keiichiro Watanabe, Masahiro Hiasa, Qu Cui, Takeshi Harada, Shiro Fujii, Ayako Nakano, Kumiko Kagawa, Kyoko Takeuchi, ichiro Ken Yata, Akira Sakai, Masahiro Abe and Toshio Matsumoto : KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts, British Journal of Haematology, 155, 3, 328-339, 2011.
(要約)
The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)-Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time- and dose-dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra-bone injection of INA-6 cells to subcutaneously implanted rabbit bones (SCID-rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID-rab model. These results suggest that KRN5500 exerts anti-MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.
Multiple myeloma (MM) cells stimulate osteoclastogenesis, and osteoclasts (OCs) in turn enhance MM growth and drug resistance, resulting in a vicious cycle. Vγ9Vδ2 T cells exert potent anti-tumor effects, making T cell-based immunotherapies using these cells attractive candidates for currently incurable malignancies, such as MM. However, the impact of such treatments on the MM-OC interaction is largely unknown. We demonstrate here that Vγ9Vδ2 T cells expanded by zoledronic acid and IL-2 exerted potent cytotoxic effects on both MM cells and OCs, even in coculture settings, but showed no such effect on bone marrow stromal cells. Vγ9Vδ2 T cells marginally affected colony formation from normal hematopoietic progenitors, and furthermore migrated toward osteopontin and MIP-1α, factors produced by the MM-OC interaction. These results suggest that Vγ9Vδ2 T cells expanded by zoledronic acid and IL-2 are able to migrate to MM bone lesions and preferentially target OCs as well as MM cells, thereby inhibiting both tumor expansion and bone destruction.
Ayako Nakano, Masahiro Abe, Asuka Oda, Hiroe Amou, Masahiro Hiasa, Shingen Nakamura, Hirokazu Miki, Takeshi Harada, Shirou Fujii, Kumiko Kagawa, Kyoko Takeuchi, Takashi Watanabe, Shuji Ozaki and Toshio Matsumoto : Delayed treatment with vitamin C and N-acetyl-l-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib, International Journal of Hematology, 93, 6, 727-735, 2011.
(要約)
Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects of bortezomib without compromising its anti-myeloma effects. Schwann cells underwent macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C or N-acetyl-L-cysteine (NAC) achieved near-complete rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells. These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN.
(キーワード)
Bortezomib-induced peripheral neuropathy / Myeloma / N-Acetyl-l-cysteine / Vitamin C
J. Asano, A. Nakano, A. Oda, H. Amou, M. Hiasa, K. Takeuchi, H. Miki, S. Nakamura, Takeshi Harada, S. Fujii, K. Kagawa, I. Endo, K. Yata, A. Sakai, S. Ozaki, T. Matsumoto and M. Abe : The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells, Leukemia, 25, 7, 1182-1188, 2011.
(要約)
Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFα, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-κB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.
A 67-year-old man was diagnosed with multiple myeloma IgA-lambda type, Durie-Salmon classification stage IIIA in October 2001. He received five courses of induction chemotherapy consisting of vincristine, doxorubicin and dexamethasone and then underwent high dose chemotherapy followed by autologous stem cell transplantation in March 2003. He achieved partial response, but then relapsed after treatment with thalidomide and was admitted to our hospital in June 2007. The patient was complicated by tumor lysis syndrome (TLS) after receiving bortezomib therapy twice. Computed tomography after bortezomib therapy showed the rapid appearance of tumors in the right upper lobe of the lung, tail of the pancreas and the spleen. Though he was treated with antifungal agents, micafungin and voriconazole, he died eighty-five days after admission. Autopsy specimen showed fungal clumps and hemorrhagic infarction in the lung and spleen, and vegetation at the mitral valve was the same fungus as found in the lung. We diagnosed disseminated zygomycosis based on the pathological fungal morphology. This case suggested that metabolic acidosis was caused by TLS, while poorly controlled diabetes, secondary hemochromatosis due to transfusion, and breakthrough zygomycosis during antifungal therapy were thought to be factors contributing to the development of zygomycosis.
Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions, in which bone formation is impaired and osteoclastic bone resorption is enhanced. TGF-beta, a potent inhibitor of terminal osteoblast (OB) differentiation, is abundantly deposited in the bone matrix, and released and activated by the enhanced bone resorption in MM. The present study was therefore undertaken to clarify the role of TGF-beta and its inhibition in bone formation and tumor growth in MM. TGF-beta suppressed OB differentiation from bone marrow stromal cells and MC3T3-E1 preosteoblastic cells, and also inhibited adipogenesis from C3H10T1/2 immature mesenchymal cells, suggesting differentiation arrest by TGF-beta. Inhibitors for a TGF-beta type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-beta inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-beta inhibition expedited OB differentiation in parallel with suppression of MM cell growth. The anti-MM activity was elaborated exclusively by terminally differentiated OBs, which potentiated the cytotoxic effects of melphalan and dexamethasone on MM cells. Furthermore, TGF-beta inhibition was able to suppress MM cell growth within the bone marrow while preventing bone destruction in MM-bearing animal models. The present study demonstrates that TGF-beta inhibition releases stromal cells from their differentiation arrest by MM and facilitates the formation of terminally differentiated OBs, and that terminally differentiated OBs inhibit MM cell growth and survival and enhance the susceptibility of MM cells to anti-MM agents to overcome the drug resistance mediated by stromal cells. Therefore, TGF-beta appears to be an important therapeutic target in MM bone lesions.
Ichi Ken Kitazoe, Masahiro Abe, Masahiro Hiasa, Asuka Oda, Hiroe Amou, Takeshi Harada, Ayako Nakano, Kyoko Takeuchi, Toshihiro Hashimoto, Shuji Ozaki and Toshio Matsumoto : Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma, International Journal of Hematology, 89, 1, 45-57, 2008.
(要約)
Multiple myeloma is still an incurable disease, most commonly occurring in the elderly. The myeloma-induced bone marrow microenvironment protects myeloma cells from drug-induced apoptosis. Therefore, the development of novel and tolerable therapeutic alternatives to overcome the drug resistance is an important clinical issue. Valproic acid (VPA), a safe and widely used anti-epileptic agent, is revisited as a class I- and IIa-specific histone deacetylase inhibitor. In the present study, we evaluated the effect as well as a mechanism of actions of VPA on myeloma cell growth and survival, with special reference to the myeloma-induced bone marrow microenvironment. VPA at therapeutic concentrations for epilepsy induced cell death in primary CD138-positive myeloma cells as well as myeloma cell lines, but not in CD138-negative bone marrow cells. VPA suppressed osteoclastogenesis as well as osteoclast-mediated myeloma cell growth. VPA also inhibited vascular tubule formation enhanced by co-cultures of myeloma cells and osteoclasts in concert with thalidomide. In addition, VPA induced both caspase-dependent and -independent cell death in myeloma cells, and potentiated the anti-myeloma effects of melphalan and dexamethasone. Collectively, VPA is suggested to exert multi-factorial anti-myeloma actions, and may serve as a safe adjuvant to be included in conventional chemotherapies against myeloma.
Yusaku Maeda, Shoichiro Takao, Shiori Morita, Shin Kondo, Michiko Yamashita, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Mamiko Takahashi, Shiroh Fujii, Takeshi Harada, Hirokazu Miki, Masahiro Abe and Shingen Nakamura : Quality of skeletal muscles during allogeneic stem-cell transplantation: a pilot study, BMJ Supportive & Palliative Care, 2024.
(要約)
This study investigated the muscle fat fraction (FF) and muscle-related parameters before and after allogeneic hematopoietic stem cell transplantation (HSCT). Fat and water signals were derived from the in-phase and out-of-phase MR signal intensities of the pelvis and thigh using the two-point Dixon technique. They were analysed using Synapse Vincent, and muscle quality was evaluated using the FF. The muscle mass was assessed by measuring the thigh and gluteal muscle areas using a manual trace on the MR image. The association between the muscle FF and clinical data was retrospectively determined. This study included 11 patients (6 males). Their mean age was 42.7 years, and eight had leukaemia. Eight were assessed at a mean of 65.4 days post-HSCT. The hip and thigh skeletal muscle FFs were not significantly different during HSCT. The grip and lower limb muscle strengths decreased significantly after HSCT. Patients with low FFs before transplantation tended to lose muscle strength, and the increase in FF and decrease of muscle strength were correlated. Muscle strength and quantity decrease during the early phase after HSCT, especially in patients with low FF muscles. Therefore, interventions based on muscle quality and quantity are essential.
Takeshi Harada, Masahiro Hiasa, Jumpei Teramachi and Masahiro Abe : Myeloma-Bone Interaction: A Vicious Cycle via TAK1-PIM2 Signaling, Cancers, 13, 17, 4441, Sep. 2021.
(要約)
Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL-NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1-PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1-PIM2 pathway as a pivotal therapeutic target in MM.
Takeshi Harada, Teru Hideshima and Kenneth C. Anderson : Histone deacetylase inhibitors in multiple myeloma: from bench to bedside, International Journal of Hematology, 104, 3, 300-309, Sep. 2016.
(要約)
Histone deacetylases (HDACs) deacetylate the lysine residues of both histones and non-histone proteins. Histone acetylation results in a loose local chromatin structure that regulates gene-specific transcription. Non-histone proteins can also be acetylated, leading to dynamic changes in their activity and stability. For these reasons, HDAC inhibition has emerged as a potential approach for the treatment of MM. Specifically, combination treatment with HDAC inhibitors and proteasome inhibitors or immunomodulatory drugs shows remarkable anti-MM activity in both preclinical and clinical settings. However, the clinical studies using non-selective HDAC inhibitors also cause unfavorable side effects in patients, leading us to develop more isoform- and/or class-selective HDAC inhibitors to enhance tolerability without diminishing anti-MM activity, thereby improving patient outcome in MM.
(キーワード)
Drug Therapy, Combination / Epigenomics / Histone Deacetylase Inhibitors / Humans / Immunologic Factors / Multiple Myeloma / Proteasome Inhibitors / Translational Medical Research
Takeshi Harada and Shuji Ozaki : Targeted Therapy for HM1.24 (CD317) on Multiple Myeloma Cells, BioMed Research International, 2014, 965384, Jul. 2014.
(要約)
Multiple myeloma (MM) still remains an incurable disease, at least because of the existence of cell-adhesion mediated drug-resistant MM cells and/or continuous recruitment of presumed MM cancer stem cell-like cells (CSCs). As a new alternative treatment modality, immunological approaches using monoclonal antibodies (mAbs) and/or cytotoxic T lymphocytes (CTLs) are now attracting much attention as a novel strategy attacking MM cells. We have identified that HM1.24 [also known as bone marrow stromal cell antigen 2 (BST2) or CD317] is overexpressed on not only mature MM cells but also MM CSCs. We then have developed a humanized mAb to HM1.24 and defucosylated version of the mAb to adapt to clinical practice. Moreover, we have successfully induced HM1.24-specific CTLs against MM cells. The combination of these innovative therapeutic modalities may likely exert an anti-MM activity by evading the drug resistance mechanism and eliminating presumed CSCs in MM.
Masahiro Abe, Takeshi Harada and Toshio Matsumoto : Concise review: Defining and targeting myeloma stem cell-like cells, Stem Cells, 32, 5, 1067-1073, May 2014.
(要約)
Multiple myeloma (MM) remains incurable despite recent advances in the treatment of MM. Although the idea of MM cancer stem cells (CSCs) has been proposed for the drug resistance in MM, MM CSCs have not been properly defined yet. Besides clonotypic B cells, phenotypically distinct MM plasma cell fractions have been demonstrated to possess a clonogenic capacity, leading to long-lasting controversies regarding the cells of origin in MM or MM-initiating cells. However, MM CSCs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. Targeting MM CSCs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of MM CSC-like cells.
Steric hindrance by APRIL in binding of BCMA-directed bispecific antibodies: a novel refractory mechanism of BCMA-directed immunotherapies in multiple myeloma, San Diego, Dec. 2024.
2.
Shingen Nakamura, Yusaku Maeda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Hikaru Yagi, Shiro Fujii, Takeshi Harada and Hirokazu Miki : False-positive aspergillus galactomannan test in multiple myeloma, ID week 2024, 12, Supplement_1, Los Angeles, Oct. 2024.
SooHa Kim, Jumpei Teramachi, Masahiro Hiasa, A Oda, Hirofumi Tenshin, Sou Shimizu, Emiko Nakaue, Yoshiki Higa, TANAKA Mariko, NAKAGAWA Motosumi, YAMASHITA Akimi, Takeshi Nishino, Itsuro Endo, Eiji Tanaka, Takeshi Harada, T Tominaga and Masahiro Abe : Critical roles of miR-125b-contained EV in formation of an osteoblast-induced non-permissive niche for myeloma cells, ASBMR 2024, Toronto, Sep. 2024.
4.
Takeshi Harada, Asuka Oda, Yosuke Matsushita, Ryohei Sumitani, Yusuke Inoue, Tomoyo Hara, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, Mamiko Takahashi, Kiyoe Kurahashi, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Masahiro Hiasa, Jumpei Teramachi, Toyomasa Katagiri and Masahiro Abe : ADAR1-dsRNA metabolism in myeloma cells with 1q amplification: a novel therapeutic target, 19th International Myeloma Society Annual Meeting, Aug. 2022.
5.
Kotaro Tanimoto, Masahiro Hiasa, Hirofumi Tenshin, Jumpei Teramachi, Asuka Oda, Takeshi Harada, Yoshiki Higa, Kimiko Sogabe, Masahiro Oura, Ryohei Sumitani, Tomoyo Hara, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe : Mechanical unloading promotes bone destruction and myeloma tumor expansion, Cancer and bone society young investigator symposium, Online, Feb. 2022.
6.
Hirofumi Tenshin, Takeshi Harada, Yusuke Inoue, Jumpei Teramachi, Masahiro Hiasa, Sou Shimizu, Emiko Nakaue, Kotaro Tanimoto, Yoshiki Higa, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Targeting SLAMF7 to disrupt myeloma-osteoclast interaction: elotuzumabs ADCC activity with Th1-like gamma delta T cells towards osteoclasts and myeloma cells., Cancer and bone society young investigator symposium, Feb. 2022.
7.
Takeshi Harada, Yusuke Inoue, Hirofumi Tenshin, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Masahiro Hiasa, Jumpei Teramachi and Masahiro Abe : Novel strategy of elotuzumab and zoledronic acid with Th1-like T cells against myeloma, 18th International Myeloma Workshop, Wien, Sep. 2021.
8.
Takeshi Harada, Yusuke Inoue, Hirofumi Tenshin, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Hiasa, Jumpei Teramachi and Masahiro Abe : Induction of elotuzumabs ADCC activity by Th1-like T cells towards osteoclasts as well as myeloma cells, EHA2021 Virtual Congress, Jun. 2021.
9.
Takeshi Harada and Masahiro Abe : Targeting osteoclasts and myeloma cells by CELMoDs plus zoledronic acid-inducible Th1-like γδT cells in combination with elotuzumab, The 12th JSH International Symposium 2021, May 2021.
10.
Hirofumi Tenshin, Takeshi Harada, 井上 雄介, Jumpei Teramachi, Masahiro Hiasa, 小田 明日香, Kotaro Tanimoto, Sou Shimizu, Yoshiki Higa, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Tomoko Maruhashi, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : The anti-SLAMF7 elotuzumab enhances ADCC activity with Th1-like γδT cells towards osteoclasts and myeloma cells., The European Calcified Tissue Society 2021 Digital Congress 2021, web, Mar. 2021.
11.
Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Takeshi Harada, Eiji Tanaka, Kotaro Tanimoto, Sou Shimizu, Masahiro Oura, Kimiko Sogabe, Masahiro Abe, Toshio Matsumoto and Itsuro Endo : The novel therapeutic approaches with TAK1 inhibition against the aberrant NLRP3 inflammasome activation in rheumatoid arthritis, ECTS 2020 Digital Congress, Oct. 2020.
12.
Takeshi Harada, Asuka Oda, Hiroto Ohguchi, Yohann Grondin, Hirofumi Tenshin, Masahiro Hiasa, Jumpei Teramachi, Masahiro Oura, Kimiko Sogabe, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Hirokazu Miki, Kumiko Kagawa, Shuji Ozaki, Teru Hideshima, Kenneth C. Anderson and Masahiro Abe : Novel therapeutic rationale for targeting HDAC1 and PIM2 in multiple myeloma, 61th ASH Annual Meeting & Exposition, Orlando, Dec. 2019.
Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Ashtar Mohannad, Kotaro Tanimoto, Soh Shimizu, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : The role of NLRP3 inflammasome activation in joint inflammation and destruction in rheumatoid arthritis: novel therapeutic approaches with TAK1 inhibition., 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting, Oct. 2019.
14.
Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Ashtar Mohannad, Kotaro Tanimoto, Masami Iwasa, Bat-Erdene Ariunzaya, Takeshi Harada, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : TAK1 inhibition effectively alleviates joint inflammation as well as bone destruction in rheumatoid arthritis: Suppression of NLRP3 inflammasome-mediated inflammation and osteoclastic bone resorption, American Society for Bone and Mineral Society Annual meeting 2019, Orlando, Florida, USA, Sep. 2019.
15.
Jumpei Teramachi, Soh Shimizu, Hirofumi Tenshin, Bat-Erdene Ariunzaya, Masahiro Hiasa, Kotaro Tanimoto, Oda Asuka, Takeshi Harada, Mohannad Ashtar, Kotaro Tanimoto, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe : A progressive auto-amplification loop in TAK1 expression and activation in MM cells., ASBMR 2019,, Orlando, Florida, USA., Sep. 2019.
16.
Takeshi Harada, Asuka Oda, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Oura, Kimiko Sogabe, Shiroh Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Shuji Ozaki, Teru Hideshima, C. Kenneth Anderson and Masahiro Abe : Targeting myeloma metabolisms regulated by HDAC1-IRF4 axis can be a novel therapeutic strategy, 17th International Myeloma Workshop, Sep. 2019.
17.
Mohannad Ashtar, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Kotaro Tanimoto, Oda Asuka, Iwasa Masami, Takeshi Harada, Bat-Erdene Ariunzaya, Kimiko Sogabe, Masahiro Oura, Shiroh Fujii, Kumiko Kagawa, Shingen Nakamura, Hirokazu Miki, Toshio Matsumoto, Masahiro Abe and Eiji Tanaka : Peri-implantitis and the role of Febuxostat in osteoclast differentiation., AEEDC Dubai World Orthodontic Conference, Dubai, UAE, Feb. 2019.
18.
Takeshi Harada, Asuka Oda, Yohann Grondin, Jumpei Teramachi, Ariunzaya Bat-Erdene, Masami Iwasa, Masahiro Oura, Shingen Nakamura, Kumiko Kagawa, Yasunobu Okamoto, Kimiko Sogabe, Shiroh Fujii, Hirokazu Miki, Shuji Ozaki, Teru Hideshima, Kenneth C. Anderson and Masahiro Abe : The critical role of the HDAC1-IRF4-Pim-2 axis in myeloma cell growth and survival: therapeutic impacts of targeting the HDAC1-IRF4-Pim-2 axis, 60th ASH Annual Meeting & Exposition, San Diego, Dec. 2018.
19.
Shingen Nakamura, Hirokazu Miki, Ariunzaya Bat-Erdene, Yasunobu Okamoto, Kimiko Sogabe, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Takeshi Harada, Shiroh Fujii, Kumiko Kagawa and Masahiro Abe : Alteration of muscle mass after chemotherapy in patients with newly diagnosed multiple myeloma., Esmo asia 2018, Nov. 2018.
20.
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Oda Asuka, Bat-Erdene Ariunzaya, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : Disruption of a progressive vicious cycle between myeloma tumor growth and bone destruction by TAK1 inhibition, ASBMR 2018 Annual Meeting, Montreal, Sep. 2018.
21.
Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Ashtar Mohannad, Kotaro Tanimoto, Iwasa Masami, Bat-Erdene Ariunzaya, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Opposite effects of TRAIL on the Sp-1-c-FLIP survival pathway in myeloma cells and osteoclasts., ASBMR 2018 Annual Meeting, Montreal, Sep. 2018.
22.
Takeshi Harada, Oda Asuka, Jumpei Teramachi, Bat-Erdene Ariunzaya, Iwasa Masami, Oura Masahiro, Shingen Nakamura, Kumiko Kagawa, Okamoto Yasunobu, Kimiko Sogabe, Shiroh Fujii, Hirokazu Miki, Hideshima Teru, Anderson C. Kenneth and Masahiro Abe : Selective inhibition of class-I HDAC induces myeloma cell death through targeting IRF4-Pim-2 axis, The 9th JSH International Symposium 2018 in Kyoto, Jul. 2018.
(キーワード)
Multiple myeloma / Class-I HDAC / IRF4 / Pim2
23.
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Oda Asuka, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Tatsuji Haneji, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction, 8th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone and other Musculoskeletal Diseases and Cancer and Bone Society 2018 Meeting, Oxford, Jun. 2018.
24.
Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : TAK1 inhibition impairs myeloma cell-bone marrow interaction to reduce myeloma tumor growth and bone destruction, American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting, Denver, Sep. 2017.
25.
Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction, International Society for Experimental Hematology 46th Annual Scientific Meeting, Frankfurt, Aug. 2017.
26.
Jumpei Teramachi, Masahiro Hiasa, Oda Asuka, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Akihito Yamamoto, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe : Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction, Cancer and Bone Society Conference 2017, Indianapolis, May 2017.
Takeshi Harada and Masahiro Abe : Development of immunotherapies to better control multiple myeloma: how to maximize their efficacy, 2025 the Japanese Society of Medical Oncology Annual Meeting, Mar. 2025.
Shingen Nakamura, Taiki Hori, Masafumi Nakamura, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, 高橋 真美子, Shiroh Fujii, Hirokazu Miki, Takeshi Harada and Masahiro Abe : Humoral response of the mRNA vaccine against SARS-CoV-2 in patients with plasma cell dyscrasia, The 47th annual meeting of Japanese Society of Myeloma, May 2022.
Sou Shimizu, Jumpei Teramachi, Takeshi Harada, 小田 明日香, Hirofumi Tenshin, Masahiro Hiasa, Kotaro Tanimoto, Yoshiki Higa, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : The critical roles of the TAK1-CIP2A axis in MM cell growth and survival and osteoclastogensis, 第83回日本血液学会学術集会, BPA-3-3, Sep. 2021.
56.
曽我部 公子, 原田 武志, 中村 信元, 三木 浩和, 小田 明日香, 井上 雄介, 住谷 龍平, 丸橋 朋子, 大浦 雅博, 藤井 志朗, 賀川 久美子, 天眞 寛文, 日浅 雅博, 寺町 順平, 安倍 正博 : PIMとAkt阻害は骨髄腫細胞におけるプロテアソーム阻害薬感受性を増強する, The 83rd Annual Meeting of the Japanese Society of Hematology, 2021年9月.
57.
Yoshiki Higa, Masahiro Hiasa, Hirofumi Tenshin, Jumpei Teramachi, Takeshi Harada, 小田 明日香, 大浦 雅弘, Kimiko Sogabe, Itsuro Endo, Toshio Matsumoto, Masahiro Abe and Eiji Tanaka : Critical roles of the XO-ROS axis in the pathology of bone loss in myeloma, 第83回日本血液学会学術集会, BPA-3-4, Sep. 2021.
Hirofumi Tenshin, アシテル モハナッド, Jumpei Teramachi, Masahiro Hiasa, Kotaro Tanimoto, Sou Shimizu, 比嘉 佳基, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : 抗腫瘍薬が誘導するROSは破骨細胞分化を促進する Xanthine oxidase阻害剤febuxostatの治療効果, The Annual Meeting of the Japanese Society for Bone and Mineral Research Program & Abstracts, 148, Oct. 2020.
原田 武志, Oda Asuka, 天眞 寛文, 寺町 順平, 大浦 雅博, 曽我部 公子, 岩佐 昌美, 藤井 志朗, 三木 浩和, 賀川 久美子, 秀島 輝, Anderson C. Kenneth, 安倍 正博 : The novel therapeutic strategy targeting the HDAC1-IRF4-PIM2 pathway in myeloma cells, The 44th Annual Meeting of the Japanese Society of Myeloma, 2019年5月.
(キーワード)
Multiple myeloma / Class-I HDAC / IRF4 / Pim-2
93.
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Oda Asuka, Bat-Erdene Ariunzaya, Takeshi Harada, Iwasa Masami, Shiroh Fujii, Kimiko Sogabe, Shingen Nakamura, Hirokazu Miki, Masahiro Oura, Kumiko Kagawa, Itsuro Endo, Toshio Matsumoto and Masahiro Abe : Mechanisms of TAK1 over-activation in myeloma cells and TAK1-mediated myeloma growth and bone destruction, 第80回日本血液学会学術集会, Oct. 2018.
94.
Takeshi Harada : Roles of HDAC1 and HDAC3 as therapeutic targets against myeloma cells, The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
Ashtar Mohannad, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Kotaro Tanimoto, Oda Asuka, Iwasa Masami, Takeshi Harada, Ariunzaya Erdene Bat, Kimiko Sogabe, Oura Masahiro, Shiroh Fujii, Kumiko Kagawa, Shingen Nakamura, Hirokazu Miki, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Roles of ROS in induction of bone disease and cancer treatment-induced bone loss in myeloma., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
97.
Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Kotaro Tanimoto, Mohannad Ashtar, Ariunzaya Bat-Erdene, Iwasa Masami, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Kimiko Sogabe, Oura Masahiro, Shiroh Fujii, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Inverse regulation of c-FLIP-mediated survival in myeloma cells and osteoclasts by TRAIL., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
98.
Kotaro Tanimoto, Masahiro Hiasa, Hirofumi Tenshin, Jumpei Teramachi, Oda Asuka, Mohannad Ashtar, Ariunzaya Bat-Erdene, Iwasa Masami, Kimiko Sogabe, Oura Masahiro, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : Impact of denervation-induced paralysis and mechanical unloading on tumor expansion in myeloma., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
99.
Masahiro Hiasa, Jumpei Teramachi, Hirofumi Tenshin, Kotaro Tanimoto, Ariunzaya Bat-Erdene, Mohannad Ashtar, Masami Iwasa, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Kimiko Sogabe, Oura Masahiro, Shiroh Fujii, Kumiko Kagawa, Oda Asuka, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe : The effects of cathepsin K inhibition on osteocytes: its role in bone restoration in MM bone disease., The 80th Annual Meeting of the Japanese Society of Hematology, Oct. 2018.
岩佐 昌美, 原田 武志, Ariunzaya Bat-Erdene, 小田 明日香, 前田 悠作, 高橋 真美子, 大浦 雅博, 寺町 順平, 藤井 志朗, 中村 信元, 三木 浩和, 賀川 久美子, 安倍 正博 : パノビスタットによる骨髄腫細胞のIFN-γ-STAT1- PD-L1経路の増強, The 43rd Annual Meeting of the Japanese Society of Myeloma, 2018年5月.
(キーワード)
Multiple myeloma
105.
原田 武志, Oda Asuka, 寺町 順平, Bat-Erdene Ariunzaya, 岩佐 昌美, Maeda Yusaku, 中村 信元, Oura Masahiro, 藤井 志朗, 三木 浩和, 賀川 久美子, Hideshima Teru, Anderson C. Kenneth, 安倍 正博 : HDAC1/3 inhibition disrupts the IRF4-Pim-2 pathway to induce effective myeloma cell death, The 43rd Annual Meeting of the Japanese Society of Myeloma, 2018年5月.
Takeshi Harada, Ohguchi Hiroto, Grondin Yohann, Kikuchi Shohei, Sagawa Morihiko, Tai Yu-Tzu, Mazitschek Ralph, Hideshima Teru and Anderson C. Kenneth : HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications, The 79th Annual Meeting of the Japanese Society of Hematology, Oct. 2017.
(キーワード)
Multiple myeloma / HDAC3 / DNMT1
108.
寺町 順平, 森 裕史, 越智 保夫, 天知 良太, 小田 明日香, 日浅 雅博, 原田 武志, 藤井 志朗, 中村 信元, 三木 浩和, 賀川 久美子, 遠藤 逸朗, 田中 栄二, 松本 俊夫, 安倍 正博 : Potent induction of bone formation by anti-resorptive cathepsin K inhibitor in myeloma., 第77回日本血液学会学術集会,, 2016年10月.