研究等業績 - 原著論文 - 髙橋 直人
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Ezawa T.
FASEB Journal ( FASEB Journal ) 39 ( 1 ) e70296 2025年01月
研究論文（学術雑誌）
Various tubular diseases in patients with multiple myeloma (MM) are caused by monoclonal immunoglobulin light chains (LCs). However, the physicochemical characteristics of the disease-causing LCs contributing to the onset of MM-associated tubular diseases remain unclear. We herein report a rare case of MM-associated combined tubulopathies: non-crystalline light chain proximal tubulopathy (LCPT) and crystalline light chain cast nephropathy (LCCN). The patient's urinary κ-LC (Bence-Jones proteins, BJP-κ PT-CN) was detected through immunofixation. Renal biopsy revealed cytoplasmic vacuoles in swollen proximal tubular cells and distal tubular casts. Immunohistochemistry showed proximal tubular reabsorption granules and distal tubular casts positively stained with an anti-κ-LC antibody. Electron microscopy identified vacuolation and an increased number of lysosomes in proximal tubular epithelial cells without crystalline structures. Distal tubular casts comprised numerous crystals with both rod-shaped and needle-like configurations and tube-shaped materials. To elucidate the molecular mechanisms underlying tubular toxicity, we performed the following physicochemical analyses of BJP-κ PT-CN: N-terminal amino acid sequencing, cDNA cloning, size-exclusion chromatography, thermal shift assays, and X-ray crystallography. The variable segment of BJP-κ PT-CN was derived from the IGKV1-39 gene. The characteristic features of BJP-κ PT-CN were a positively charged surface patch, concentration-dependent monomer-dimer equilibrium, and the R61G mutation. This is the first biochemical and structural characterization of disease-causing BJPs in MM-associated LCPT and crystalline LCCN. The results obtained suggest that these characteristic features enhance protein binding to negatively charged sites on brush-border membranes in proximal tubules and promote the formation of organized casts in distal tubular lumens.
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Abumiya M.
International Journal of Hematology ( International Journal of Hematology ) 2025年
研究論文（学術雑誌）
Bosutinib is known to increase serum creatinine levels, and its mechanism of action is believed to involve a decrease in tubular creatinine excretion due to inhibition of tubular transporters and organic cation transporter 2. This study aimed to determine whether discontinuation of bosutinib could reverse bosutinib-induced elevation of serum creatinine levels. Serum creatinine levels were compared immediately before and after bosutinib administration and after bosutinib discontinuation in 11 patients with chronic myeloid leukemia. The median serum creatinine concentration significantly increased from 0.66 mg/dL before bosutinib to 0.76 mg/dL after bosutinib (P = 0.003) and decreased from 0.79 mg/dL before discontinuation of bosutinib to 0.66 mg/dL after discontinuation of bosutinib at 3 months (P = 0.005). This study revealed that bosutinib-induced elevation of serum creatinine, which was more pronounced in patients with the SLC22A2 808G/G genotype, does not indicate chronic kidney disease, but rather is simply a laboratory abnormality. If bosutinib-induced chronic kidney disease is suspected, renal function should be assessed by urinalysis and cystatin C levels to differentiate from simple elevation of serum creatinine.
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Ureshino H.
International Journal of Hematology ( International Journal of Hematology ) 120 ( 4 ) 492 - 500 2024年10月
研究論文（学術雑誌）
Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.
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Matsumura I.
Blood Advances ( Blood Advances ) 8 ( 20 ) 5237 - 5247 2024年10月
研究論文（学術雑誌）
Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequite condition for TFR. The Japan Adult Leukemia Study Group (JALSG) conducted a multicentral prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of MR4.5 (international scale [IS] BCR::ABL1≤0.0032%) by 18 months between nilotinib and dasatinib as a primary endpoint. A total of 454 patients were randomly assigned to the nilotinib 300 mg, bid arm or dasatinib 100 mg, qd arm (both, n=227). BCR::ABL1 mRNA levels were monitored every three months. Study treatment was stopped if the patients were judged as failure by the European LekemiaNet (ELN) 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI]: 26.5-39.1%) in the nilotinib arm and 30.8% (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference (p=0.66). Also, the cumulative achievement rates of early molecular response (EMR), complete cytogenetic response (CCyR) and major molecular response (MMR), MR4.0 by 12, 18, 24, and 36 months were almost the same between the two arms. At 36 months, 66.5% and 65.0% patients continued nilotinib and dasatinib, respectively (p=0.76). There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two arms by log-rank tests (PFS, p=0.58; OS, p=0.64). These results suggest that nilotinib and dasatinib would be equally effective for de novo CML-CP patients with similar continuity. UMIN Clinical Trials Registry (#UMIN000007909).
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Ayano Saito, Yoshihiro Kameoka, Kumi Ubukawa, Hiroshi Ohtani, Fumito Abe, Masaya Saito, Mako Hashimoto, Tatsuro Kanazawa, Atsushi Komatsuda, Naoto Takahashi
Internal medicine (Tokyo, Japan) ( 一般社団法人 日本内科学会 ) advpub ( 0 ) 1388 - 1392 2024年10月
研究論文（学術雑誌）
A 71-year-old woman developed nephrotic syndrome during 10-year follow-up for chronic lymphocytic leukemia. A renal biopsy sample analysis revealed IgG1-lambda-positive monoclonal immunotactoid glomerulopathy (mITG). The patient was treated with ibrutinib, a Bruton tyrosine kinase inhibitor, and complete renal remission was achieved after 24 months. ITG is a rare disease that is characterized by glomerular deposition. In particular, mITG, which presents immune deposits that exhibit light-chain restriction, is often associated with hematologic disorders. Most patients with mITG receive immunosuppressive therapy and/or chemotherapy; however, to our knowledge, there have been no reports of treatment with ibrutinib.
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Yamada M.
International Journal of Hematology ( International Journal of Hematology ) 120 ( 3 ) 325 - 336 2024年09月
研究論文（学術雑誌）
Basic research to expand treatment options for multiple myeloma is greatly needed due to the refractory nature of the disease. Histone deacetylase (HDAC) inhibitors, which are epigenetic regulators, are attractive but have limited applications. MicroRNAs (miRNAs), which are also epigenetic regulators, are important molecules that may lead to future therapeutic breakthroughs. In this study, we comprehensively searched for miRNAs that are altered by HDAC inhibitors in myeloma cells. We identified miR-7-5p (miR-7) as a miRNA downregulated by HDAC inhibitors. Transfection of myeloma cell lines with miR-7 suppressed cell proliferation, induced apoptosis, and enhanced the effects of the HDAC inhibitor panobinostat. Expression of miR-7 was downregulated by c-Myc inhibition, but upregulated by bortezomib. Comprehensive examination of miR-7 targets revealed four candidates: SLC6A9, LRRC59, EXOSC2, and PSME3. Among these, we focused on PSME3, an oncogene involved in proteasome capacity in myeloma cells. PSME3 knockdown increases myeloma cell death and panobinostat sensitivity. In conclusion, miR-7, which is downregulated by HDAC inhibitors, is a tumor suppressor that targets PSME3. This miR-7 downregulation may be involved in HDAC inhibitor resistance. In addition, combinations of anti-myeloma drugs that complement changes in miRNA expression should be considered.
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OA-35 Discovery of a Novel Class MMSET Inhibitor With Specificity for t(4; 14)-Positive Multiple Myeloma
Sae Matsuoka, Naoki Osada, Hirokazu Kubota, Ko Kikuzato, Hiroo Koyama, Takeshi Sonoda, Akiko Ide, Minoru Yoshida, Masaki Kikuchi, Takashi Umehara, Chiduru Watanabe, Teruki Honma, Hiroshi Yasui, Sho Ikeda, Naoto Takahashi, Hideki Nakasone, Jiro Kikuchi, Yusuke Furukawa
Clinical Lymphoma Myeloma and Leukemia ( Elsevier BV ) 24 S22 - S23 2024年09月
研究論文（学術雑誌）
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Kobayashi T.
Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology ) 94 ( 2 ) 285 - 296 2024年08月
研究論文（学術雑誌）
PURPOSE: An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. METHODS: The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. RESULTS: Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). CONCLUSION: Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.
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Kobayashi T.
Xenobiotica ( Xenobiotica ) 55 ( 1 ) 1 - 6 2024年
研究論文（学術雑誌）
The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.
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Oyake T.
Journal of Clinical and Experimental Hematopathology ( Journal of Clinical and Experimental Hematopathology ) 64 ( 3 ) 191 - 202 2024年
研究論文（学術雑誌）
Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.
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Ponatinib Improved the Prognosis of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Japanese Single-Center Cohort Study.
Nagi Tozawa, Takaya Yamashita, Miho Nara, Yuki Fujioka, Sho Ikeda, Takahiro Kobayashi, Isuzu Kobayashi, Akihiro Kitadate, Yoshihiro Kameoka, Naoto Takahashi
Cureus 15 ( 12 ) e50416 2023年12月
研究論文（学術雑誌）
Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluate the outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OS was 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%; P=0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22; P=0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, P=0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily need to receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.
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Kazuaki Kameda, Ryo Yanagiya, Yuji Miyatake, Joaquim Carreras, Hiroshi Higuchi, Hiromichi Murayama, Takashi Ishida, Asahi Ito, Shinsuke Iida, Noriko Fukuhara, Hideo Harigae, Yuki Fujioka, Naoto Takahashi, Hidenori Wada, Fumihiro Ishida, Hideyuki Nakazawa, Rei Ishihara, Yuki Murakami, Hiroyuki Tagawa, Tadashi Matsuura, So Nakagawa, Sadahiro Iwabuchi, Shinichi Hashimoto, Ken-Ichi Imadome, Naoya Nakamura, Kenichi Ishizawa, Yoshinobu Kanda, Kiyoshi Ando, Ai Kotani
Blood Journal ( American Society of Hematology ) 2023年05月
研究論文（学術雑誌）
Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established three ANKL-patient-derived xenograft mice (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a non-canonical hematopoietic organ in adults, serves as a principal niche for ANKL, and that inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.
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Abe K.
Cancer Medicine ( Cancer Medicine ) 12 ( 8 ) 9709 - 9722 2023年
研究論文（学術雑誌）
BACKGROUND: Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. METHODS: We performed cDNA microarray analysis for SP and non-SP obtained from RPMI-8226 and KMS-11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2 ). Genes specifically upregulated in hypoxic SP were examined. RESULTS: Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein-coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase-1 (HMOX1/HO-1) is induced by hypoxia-inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia-induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. CONCLUSION: These results suggest that the hypoxia-ROS-HMOX1 axis and hypoxia-induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments.
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Abumiya M.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 2 ) 382 - 387 2021年04月 [査読有り]
研究論文（学術雑誌） 国内共著
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Abumiya M.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 1 ) 219 - 222 2021年02月 [査読有り]
研究論文（学術雑誌） 国内共著
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Ito F.
International Journal of Hematology ( International Journal of Hematology ) 113 ( 1 ) 100 - 105 2021年01月 [査読有り]
研究論文（学術雑誌） 国内共著
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Teshima Kazuaki, Kume Masaaki, Kondo Rui, Shibata Kenichi, Abe Ko, Aono Hiroaki, Fushimi Susumu, Takahashi Satoshi, Takahashi Satsuki, Saito Masahiro, Takahashi Naoto
Internal Medicine ( 一般社団法人 日本内科学会 ) 2021年 [査読有り]
研究論文（学術雑誌） 国内共著
<p>A 17-year-old girl was diagnosed with acute lymphoblastic leukemia (ALL). After the administration of high-dose methotrexate (MTX) or intrathecal MTX, the patient experienced transient hemiparesis and motor aphasia. Diffusion-weighted magnetic resonance imaging showed a high-intensity lesion in the bilateral centrum semiovale, and a vasospasm was detected in the proximal segment of bilateral A1 on magnetic resonance angiography. Edaravone was administered, and leucovorin rescue treatment was continued; eventually, the patient's neurological symptoms completely resolved. This finding suggested that vasospasm might be a mechanism underlying MTX-induced transient encephalopathy in adolescent and young adult patients with ALL. </p>
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Ubukawa K.
Scientific Reports ( Scientific Reports ) 10 ( 1 ) 11806 2020年12月 [査読有り]
研究論文（学術雑誌） 国内共著
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Outcome of colorectal cancer in Diamond–Blackfan syndrome with a ribosomal protein S19 mutation
Kimura K.
Clinical Journal of Gastroenterology ( Clinical Journal of Gastroenterology ) 13 ( 6 ) 1173 - 1177 2020年12月 [査読有り]
研究論文（学術雑誌） 国内共著
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Ikeda S.
Cancer Science ( Cancer Science ) 111 ( 11 ) 4088 - 4101 2020年11月 [査読有り]
研究論文（学術雑誌） 国内共著
Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells and existing in bone marrow region. Recent developments in the field of myeloma onco-biology enabled to use proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis against myeloma cells. However, PI cannot kill all of myeloma cells. One reason of this might be activation of autophagy via hypoxic stress under bone marrow microenvironment. Hypoxia-inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI-resistant myeloma cells. Here, we demonstrate that a hypoxia-inducible glycolytic enzyme hexokinase-2 (HK2) contributes to acquisition of the anti-apoptotic phenotype of myeloma cells via activating autophagy. We found that hypoxic stress led to autophagy activation with upregulation of HK2 in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. We examined the cooperative effects of PI (bortezomib) against immunodeficient mice inoculated with HK2-knocked down myeloma cells and observed significant tumor reduction. An HK2 inhibitor, 3-bromopyruvate, also induced apoptosis under hypoxia rather than normoxic conditions. Further examination of the cooperative effects of both 3-bromopyruvate and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggest that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Furthermore, cooperative treatment against a dominant fraction with PI and a minor fraction adapting to the bone marrow microenvironment with HK2 inhibitor may lead to deeper remission for refractory MM.