Updated on 2025/01/05

Information

 

写真a

 
HATAKEYAMA KIWAMU
 
Organization
Kyushu University Hospital Emergency & Critical Care Center Assistant Professor
School of Medicine Department of Medicine(Concurrent)
Title
Assistant Professor
Profile
救命救急センターにて救急疾患を中心に診療に従事している。
External link

Research Interests・Research Keywords

  • Research theme:Research of thromboembolism and cardiotoxicity related to cancer therapy.

    Keyword:IMiDs-induced thromboembolism, anthracycline-induced cardiotoxicity

    Research period: 2017.4 - 2025.3

Papers

  • Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug–induced thromboembolism Reviewed International journal

    8 ( 3 )   785 - 796   2024.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

    DOI: 10.1182/bloodadvances.2023010080.

  • TET2 Clonal Hematopoiesis is Associated with Anthracycline-Induced Cardiotoxicity in Patients with Lymphoma Reviewed International journal

    Kiwamu Hatakeyama, Michinari Hieda, Yuichiro Semba, Shohei Moriyama, Yuqing Wang, Takahiro Maeda, Koji Kato, Toshihiro Miyamoto, Koichi Akashi, Yoshikane Kikushige

    JACC: CardioOncology   4 ( 1 )   141 - 143   2022.3   ISSN:26660873 eISSN:26660873

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    Language:English   Publishing type:Research paper (scientific journal)  

    Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM.

    DOI: 10.1016/j.jaccao.2022.01.098

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    CiNii Research

    Repository Public URL: https://hdl.handle.net/2324/6789521

  • Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug-induced thromboembolism

    Hatakeyama, K; Kikushige, Y; Ishihara, D; Yamamoto, S; Kawano, G; Tochigi, T; Miyamoto, T; Sakoda, T; Christoforou, A; Kunisaki, Y; Fukata, M; Kato, K; Ito, T; Handa, H; Akashi, K

    BLOOD ADVANCES   8 ( 3 )   785 - 796   2024.2   ISSN:2473-9529 eISSN:2473-9537

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    Language:English   Publisher:Blood Advances  

    Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

    DOI: 10.1182/bloodadvances.2023010080

    Web of Science

    Scopus

    PubMed

  • Emphysematous pyelonephritis with ST elevation accompanied by reciprocal changes mimicking acute coronary syndrome Reviewed International journal

    Kiwamu Hatakeyama, Yuji Shono, Takuma Hashimoto, Taiki Sakamoto, Masaaki Nishihara, Takeshi Iyonaga, Soichi Mizuguchi, takafumi sakamoto, Jun Maki, Tomohiko Akahoshi

    American Journal of Emergency Medicine   70   208.e5 - 208.e7   2023.8

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    Language:English   Publishing type:Research paper (scientific journal)  

  • Emphysematous pyelonephritis with ST elevation accompanied by reciprocal changes mimicking acute coronary syndrome

    Hatakeyama, K; Shono, Y; Hashimoto, T; Sakamoto, T; Nishihara, M; Iyonaga, T; Mizuguchi, S; Sakamoto, T; Maki, J; Akahoshi, T

    AMERICAN JOURNAL OF EMERGENCY MEDICINE   70   208e5 - 208e7   2023.8   ISSN:0735-6757 eISSN:1532-8171

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    Language:English   Publisher:American Journal of Emergency Medicine  

    Patients with infectious diseases including sepsis can develop ST segment changes on an electrocardiogram (ECG) in the absence of coronary artery disease. However, ST elevation with “reciprocal ST segment depression (RSTD)”, which is recognized as a specific finding for ST-elevated myocardial infarction, is rare in such patients. Although a small number of cases have reported ST-segment elevation in gastritis, cholecystitis, and sepsis, regardless of coronary artery disease, none presented with reciprocal changes. Here, we describe a rare case of a patient with emphysematous pyelonephritis complicating septic shock who developed ST elevation accompanied by reciprocal changes with no coronary occlusion. Emergency physicians should consider the possibility of acute coronary syndrome mimicking, and choose non-invasive diagnostic procedures when investigating the causes of ECG abnormalities associated with critically ill patients.

    DOI: 10.1016/j.ajem.2023.06.038

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  • Human acute leukemia uses branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function

    Kikushige, Y; Miyamoto, T; Kochi, Y; Semba, Y; Ohishi, M; Irifune, H; Hatakeyama, K; Kunisaki, Y; Sugio, T; Sakoda, T; Miyawaki, K; Kato, K; Soga, T; Akashi, K

    BLOOD ADVANCES   7 ( 14 )   3592 - 3603   2023.7   ISSN:2473-9529 eISSN:2473-9537

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    Language:English   Publisher:Blood Advances  

    Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia–specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

    DOI: 10.1182/bloodadvances.2022008242

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  • TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia

    Sakoda, T; Kikushige, Y; Miyamoto, T; Irifune, H; Harada, T; Hatakeyama, K; Kunisaki, Y; Kato, K; Akashi, K

    BLOOD ADVANCES   7 ( 10 )   2053 - 2065   2023.5   ISSN:2473-9529 eISSN:2473-9537

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    Language:English   Publisher:Blood Advances  

    The activation of β-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. Aberrant β-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL receptor–related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally active in immature LSCs compared with TIM-3–expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates β-catenin via autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.

    DOI: 10.1182/bloodadvances.2022008405

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  • Natural history of severe aortic stenosis in elderly heart failure patients who declined transcatheter aortic valve implantation

    Hieda, M; Futami, S; Tanaka, H; Moriyama, S; Masui, S; Kisanuki, M; Hatakeyama, K; Irie, K; Yokoyama, T; Fukata, M; Arita, T; Maruyama, T; Nomura, H; Akashi, K

    EUROPEAN HEART JOURNAL   43   2548 - 2548   2022.10   ISSN:0195-668X eISSN:1522-9645

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Presentations

  • COVID-19重症肺炎を合併した妊婦に対して腹臥位療法を行った1例

    畠山 究、徳田 賢太郎、安藤 太一、高橋 慶多、十時 崇彰、彌永 武史、西原 正章、生野 雄二、牧 盾、赤星 朋比古

    第49回日本集中治療医学会学術集会  2022.3 

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    Event date: 2022.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:仙台   Country:Japan  

    【背景】 COVID-19第5波の波及に伴い、妊婦においてもCOVID-19肺炎を合併する症例が散見されるようになり、その一部は人工呼吸を含む集中治療を必要としている。
    【症例】38歳女性、妊娠27週。SARS-CoV-2家庭内感染によりCOVID-19に罹患した。発症7日目、酸素化障害のため入院し、高流量酸素療法を実施した。発症11日目、酸素化悪化のため集中治療室で人工呼吸管理を開始した。ICU入室時より、助産師・産科医による胎児心拍モニタリングを毎日実施し、胎児の健常性を確認した。また酸素化増悪時のVV-ECMO導入条件、帝王切開による妊娠帰結のタイミング、出生後の新生児の収容病棟について、産科・新生児科・感染制御部門・手術部門と打ち合わせを行った。胎児への酸素供給を考慮し、非妊婦の場合よりも高い動脈血酸素飽和度を維持するように呼吸管理を行った。当初、腹臥位療法の実施はためらわれ頭高位・側臥位での管理を行ったが、次第に酸素化が悪化したため、ICU入室3日目より筋弛緩併用深鎮静下に腹臥位療法を開始し、入室9日目まで継続した。腹臥位療法中は腹部の除圧ができるよう極軽度半身を浮かした状態を保持し、超音波診断装置による胎児観察も可能となるよう工夫した。次第に呼吸状態の改善を認め、入室11日目に人工呼吸器を離脱した。入室18日目(妊娠30週)、胎児の発育に問題ない状態でICUを退室した。
    【結語】COVID-19肺炎による重症呼吸不全の呼吸管理として、腹臥位療法は標準的手法となっており、妊婦においても、その安全性や有効性に関する報告が増えている。本症例においても、増大した子宮・発育した胎児への圧迫が最小限となるよう配慮した上での、腹臥位療法の実施が有効であった。また、母体の救命を第一に考えながらも、可能な限り胎児の救命も目指す必要があり、関連する診療科・多職種での連携が重要であった。

  • TET2 Clonal Hematopoiesis Represents a Strong Risk Factor for Anthracycline-Induced Cardiotoxicity in Lymphoma Patients

    2022.3 

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    Event date: 2022.3

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  • 院外心停止に対するECPRにおける経食道心エコーの有用性についての検討

    高橋 慶多, 高森 信之介, 大屋 皆既, 崎村 正太郎, 畠山 究, 彌永 武史, 西原 正章, 赤星 朋比古, 牧 盾, 山浦 健

    日本集中治療医学会雑誌  2023.6  (一社)日本集中治療医学会

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    Language:Japanese  

  • 脂肪塞栓症候群に合併した循環不全に一酸化窒素吸入が奏功した一例

    陣林 秀紀, 畠山 究, 籾井 健太, 吉本 将和, 桑原 正成, 彌永 武史, 西原 正章, 生野 雄二, 牧 盾, 中島 康晴, 赤星 朋比古

    日本救急医学会雑誌  2022.10  (一社)日本救急医学会

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    Language:Japanese  

  • 気胸を合併したCOVID-19重症肺炎の臨床的特徴についての検討

    山本 悠造, 畠山 究, 彌永 武史, 西原 正章, 生野 雄二, 賀来 典之, 牧 盾, 徳田 賢太郎, 赤星 朋比古, 北園 孝成

    日本集中治療医学会雑誌  2022.11  (一社)日本集中治療医学会

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  • 冠血流異常がないにも関わらず、対側性変化を伴うST上昇を呈し、STEMIとの鑑別を要した気腫性腎盂腎炎の一例

    橋本 卓磨, 生野 雄二, 畠山 究, 松岡 若利, 水口 壮一, 籾井 健太, 彌永 武史, 西原 正章, 賀来 典之, 牧 盾, 赤星 朋比古

    日本救急医学会雑誌  2023.12  (一社)日本救急医学会

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  • トロンボエラストグラフィ(TEG)は抗血栓療法を受けている患者の集中管理に有用である 2例の報告(Thromboelastography(TEG) is Useful for the Intensive Management of Patients Receiving Antithrombotic Therapy: Report of Two Cases)

    彌永 武史, 西原 正章, 畠山 究, 筒井 裕之

    日本循環器学会学術集会抄録集  2023.3  (一社)日本循環器学会

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    Language:English  

  • TET2クローン性造血はリンパ腫患者におけるアントラサイクリン誘発性心毒性の強力なリスク因子である(TET2 Clonal Hematopoiesis Represents a Strong Risk Factor for Anthracycline-Induced Cardiotoxicity in Lymphoma Patients)

    Hatakeyama Kiwamu, Kikushige Yoshikane, Semba Yuichirou, Moriyama Shohei, Harada Takuya, Wang Yuqing, Katou Kouji, Maeda Takahiro, Kunisaki Yuya, Fukata Mitsuhiro, Miyamoto Toshihiro, Hieda Michinari, Akashi Koichi

    日本循環器学会学術集会抄録集  2022.3  (一社)日本循環器学会

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  • Gustilo III B橈骨遠位端開放骨折に脊椎破裂骨折による大量血胸を合併した1例

    籾井 健太, 赤星 朋比古, 牧 盾, 賀来 典之, 生野 雄二, 西原 正章, 彌永 武史, 水口 壮一, 松岡 若利, 賣豆紀 智美, 畠山 究

    日本救急医学会雑誌  2023.12  (一社)日本救急医学会

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    Language:Japanese  

  • COVID-19重症肺炎を合併した妊婦に対して腹臥位療法を行った1例

    畠山 究, 徳田 賢太郎, 安藤 太一, 高橋 慶多, 十時 崇彰, 彌永 武史, 西原 正章, 生野 雄二, 牧 盾, 赤星 朋比古

    日本集中治療医学会雑誌  2022.11  (一社)日本集中治療医学会

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    Language:Japanese  

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Research Projects

  • 新日本先進医療研究財団の研究助成金 固形腫瘍における、TET2クローナル造血とがん療関連心機能障害の関連解析

    2023

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    Grant type:Donation