Kazumasa Aoyama

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy Department of Hygienic Chemistry (Shiba-Kyoritsu)

Position

Research Associate/Assistant Professor/Instructor
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Career 【 Display / hide 】

  • 2014.04
    -
    2017.06

    千葉大学医学研究院 細胞分子医学研究室（岩間厚志 教授), 特任研究員

  • 2017.07
    -
    2018.09

    千葉大学医学研究院 細胞分子医学研究室 (岩間厚志 教授), 特任助教

  • 2018.09
    -
    2021.09

    Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) (Dr. Joel Moss), Research Fellow

  • 2021.10
    -
    2023.08

    東京大学医科学研究所 幹細胞分子医学分野 (岩間厚志 教授), 特任助教

  • 2023.09
    -
    Present

    慶應義塾大学薬学部 衛生化学講座（多胡めぐみ 教授）, 助教

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Academic Background 【 Display / hide 】

  • 2003.04
    -
    2008.03

    Chiba University, 薬学部, 総合薬品科学科

    University, Graduated

  • 2008.04
    -
    2010.03

    Chiba University, 大学院医学薬学府（薬学研究院）総合薬品科学専攻, 修士課程

    Graduate School, Completed, Master's course

  • 2010.04
    -
    2014.03

    Chiba University, 大学院医学薬学府（薬学研究院）先端生命科学専攻, ４年博士課程

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士（医薬学）, Chiba University, Coursework, 2014.03

    核内 c-Abl チロシンキナーゼの機能解析：核内 F-actin bundle 形成と ヒストン脱アセチル化酵素を介したクロマチン構造変換

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Licenses and Qualifications 【 Display / hide 】

  • コーチングスキルアドバイザー(一般社団法人トラストコーチング）, 2020.11

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Research Keywords 【 Display / hide 】

  • 転写制御機構（エピジェネティック制御、ヒストン修飾、ポリコーム抑制複合体、EZH1/2）

  • 次世代シークエンス（RNA-seq、ChIP-seq、ATAC-seq、CUT&Tag etc）

  • 細胞内シグナル伝達（チロシンキナーゼ、チロシンリン酸化、ABL、JAK2、ALK）

  • がん（骨髄異形成症候群、骨髄増殖性腫瘍）

  • 創薬研究

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Papers 【 Display / hide 】

  • Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization

    Kaito S, Aoyama K, Oshima M, Tsuchiya A, Miyota M, Yamashita M, Koide S, Nakajima-Takagi Y, Kozuka-Hata H, Oyama M, Yabushita T, Ueno M, Hirao A, Tohyama K, Yamaguchi K, Furukawa Y, Kosako H, Yoshimi A, Goyama S, Nannya Y, Ogawa S, Agger K, Helin K, Koseki H, Nishiyama A, Nakanishi M, and Iwama A,

    Nature Communications (Springer Science and Business Media LLC)  15 ( 1 )  2024.08

    Research paper (scientific journal), Joint Work, Accepted

    　View Summary

    Abstract

    DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, although their therapeutic effects have been unsatisfactory. Here we show that CRISPR-Cas9 screening reveals that knockout of topoisomerase 1-binding arginine/serine-rich protein (TOPORS), which encodes a ubiquitin/SUMO E3 ligase, augments the efficacy of HMAs on myeloid leukemic cells with little effect on normal hematopoiesis, suggesting that TOPORS is involved in resistance to HMAs. HMAs are incorporated into the DNA and trap DNA methyltransferase-1 (DNMT1) to form DNA-DNMT1 crosslinks, which undergo SUMOylation, followed by proteasomal degradation. Persistent crosslinking is cytotoxic. The TOPORS RING finger domain, which mediates ubiquitination, is responsible for HMA resistance. In TOPORS knockout cells, DNMT1 is stabilized by HMA treatment due to inefficient ubiquitination, resulting in the accumulation of unresolved SUMOylated DNMT1. This indicates that TOPORS ubiquitinates SUMOylated DNMT1, thereby promoting the resolution of DNA-DNMT1 crosslinks. Consistently, the ubiquitination inhibitor, TAK-243, and the SUMOylation inhibitor, TAK-981, show synergistic effects with HMAs through DNMT1 stabilization. Our study provides a novel HMA-based therapeutic strategy that interferes with the resolution of DNA-DNMT1 crosslinks.

  • The pathogenetic significance of exhausted T cells in a mouse model of mature B cell neoplasms

    Shibamiya, A., Miyamoto-Nagai, Y., Koide, S., Oshima, M., Rizq, O., Aoyama, K., Nakajima-Takagi, Y., Kato, R., Kayamori, K., Isshiki, Y., Oshima-Hasegawa, N., Muto, T., Tsukamoto, S., Takeda, Y., Koyama-Nasu, R., Chiba, T., Honda, H., Yokote, K., Iwama, A., Sakaida, E. and Mimura, N.

    Cancer Immunol Immunother 72 ( 8 ) 2635 - 2648 2023.08

    Research paper (scientific journal), Accepted,  ISSN  0340-7004

    　View Summary

    Dysfunctional anti-tumor immunity has been implicated in the pathogenesis of mature B cell neoplasms, such as multiple myeloma and B cell lymphoma; however, the impact of exhausted T cells on disease development remains unclear. Therefore, the present study investigated the features and pathogenetic significance of exhausted T cells using a mouse model of de novo mature B cell neoplasms, which is likely to show immune escape similar to human patients. The results revealed a significant increase in PD-1(+) Tim-3(-) and PD-1(+) Tim-3(+) T cells in sick mice. Furthermore, PD-1(+) Tim-3(+) T cells exhibited direct cytotoxicity with a short lifespan, showing transcriptional similarities to terminally exhausted T cells. On the other hand, PD-1(+) Tim-3(-) T cells not only exhibited immunological responsiveness but also retained stem-like transcriptional features, suggesting that they play a role in the long-term maintenance of anti-tumor immunity. In PD-1(+) Tim-3(-) and PD-1(+) Tim-3(+) T cells, the transcription factors Tox and Nr4a2, which reportedly contribute to the progression of T cell exhaustion, were up-regulated in vivo. These transcription factors were down-regulated by IMiDs in our in vitro T cell exhaustion analyses. The prevention of excessive T cell exhaustion may maintain effective anti-tumor immunity to cure mature B cell neoplasms.

  • Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis

    Nakajima-Takagi, Y., Oshima, M., Takano, J., Koide, S., Itokawa, N., Uemura, S., Yamashita, M., Andoh, S., Aoyama, K., Isshiki, Y., Shinoda, D., Saraya, A., Arai, F., Yamaguchi, K., Furukawa, Y., Koseki, H., Ikawa, T. and Iwama, A.

    Elife 12 2023.06

    Research paper (scientific journal), Accepted,  ISSN  2050-084x

    　View Summary

    Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.

  • UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease.

    Ola Rizq, Naoya Mimura, Motohiko Oshima, Shuji Momose, Naoya Takayama, Naoki Itokawa, Shuhei Koide, Asuka Shibamiya, Yurie Miyamoto-Nagai, Mohamed Rizk, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Changshan Wang, Atsunori Saraya, Masanori Seimiya, Mariko Watanabe, Satoshi Yamasaki, Tatsuhiro Shibata, Kiyoshi Yamaguchi, Yoichi Furukawa, Tetsuhiro Chiba, Emiko Sakaida, Chiaki Nakaseko, Jun-Ichi Tamaru, Yu-Tzu Tai, Kenneth C Anderson, Hiroaki Honda, Atsushi Iwama

    Leukemia  2023.05

    Research paper (scientific journal), Accepted

    　View Summary

    UTX/KDM6A, a histone H3K27 demethylase and a key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor suppressor function remains largely uncharacterized in multiple myeloma (MM). Here, we show that the conditional deletion of the X-linked Utx in germinal center (GC) derived cells collaborates with the activating BrafV600E mutation and promotes induction of lethal GC/post-GC B cell malignancies with MM-like plasma cell neoplasms being the most frequent. Mice that developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow and extramedullary organs, serum M proteins, and anemia. Add-back of either wild-type UTX or a series of mutants revealed that cIDR domain, that forms phase-separated liquid condensates, is largely responsible for the catalytic activity-independent tumor suppressor function of UTX in MM cells. Utx loss in concert with BrafV600E only slightly induced MM-like profiles of transcriptome, chromatin accessibility, and H3K27 acetylation, however, it allowed plasma cells to gradually undergo full transformation through activation of transcriptional networks specific to MM that induce high levels of Myc expression. Our results reveal a tumor suppressor function of UTX in MM and implicate its insufficiency in the transcriptional reprogramming of plasma cells in the pathogenesis of MM.

  • A culture platform to study quiescent hematopoietic stem cells following genome editing

    Kohei Shiroshita, Hiroshi Kobayashi, Shintaro Watanuki, Daiki Karigane, Yuriko Sorimachi, Shinya Fujita, Shinpei Tamaki, Miho Haraguchi, Naoki Itokawa, Kazumasa Aoyama, Shuhei Koide, Yosuke Masamoto, Kenta Kobayashi, Ayako Nakamura-Ishizu, Mineo Kurokawa, Atsushi Iwama, Shinichiro Okamoto, Keisuke Kataoka, Keiyo Takubo

    Cell Reports Methods  2022.12

    Accepted

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Epigenetic Memories in Hematopoietic Stem and Progenitor Cells

    Aoyama, K., Itokawa, N., Oshima, M. and Iwama, A.

    Cells 11 ( 14 )  2022.07

    Lead author, Corresponding author,  ISSN  2073-4409

    　View Summary

    The recent development of next-generation sequencing (NGS) technologies has contributed to research into various biological processes. These novel NGS technologies have revealed the involvement of epigenetic memories in trained immunity, which are responses to transient stimulation and result in better responses to secondary challenges. Not only innate system cells, such as macrophages, monocytes, and natural killer cells, but also bone marrow hematopoietic stem cells (HSCs) have been found to gain memories upon transient stimulation, leading to the enhancement of responses to secondary challenges. Various stimuli, including microbial infection, can induce the epigenetic reprogramming of innate immune cells and HSCs, which can result in an augmented response to secondary stimulation. In this review, we introduce novel NGS technologies and their application to unraveling epigenetic memories that are key in trained immunity and summarize the recent findings in trained immunity. We also discuss our most recent finding regarding epigenetic memory in aged HSCs, which may be associated with the exposure of HSCs to aging-related stresses.

  • マルチフェイスな転写抑制因子 EZH2 のがん抑制修飾 (EZH2-K735me1)

    青山和正

    ファルマシア 57 (3), 230-230  2021

  • Role of EZH1 in EZH2-deficient hematopoiesis

    Aoyama K

    Nature Research Cancer Community (Invited by Editorial Office Leukemia), Online https://cancercommunity.nature.com/posts/role-of-ezh1-in-ezh2-deficient-hematopoiesis  2020.08

    Lead author, Last author, Corresponding author

  • 核内c-Ablチロシンキナーゼの新規機能：核内F-actin bundleの形成

    青山和正

    日本薬学会 生物系薬学部会 学生コロキウム 私の研究紹介, Online http://bukai.pharm.or.jp/bukai_seibutsu/pdf/research20_251204.pdf.  2013.12

    Lead author, Last author, Corresponding author

  • 慢性骨髄性白血病の新規治療戦略 ～imatinib耐性を克服するSIRT1阻害剤

    青山和正

    日本薬学会 生物系薬学部会 学生コロキウム ジャーナルクラブ, Online http://bukai.pharm.or.jp/bukai_seibutsu/pdf/journal17_240525.pdf.  2012.05

    Lead author, Last author, Corresponding author

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Presentations 【 Display / hide 】

  • Investigation of drug targets for EZH2-deficient myelodysplastic syndromes (MDS)

    青山和正 (口頭), 海渡智史, 小出周平, 御代田麻紀子, Rizq Ola, 中島やえ子, 大島基彦, 中澤洋介, 多胡めぐみ, 岩間厚志.

    第144回日本薬学会年会 (横浜) , 

    2024.03
    , 

    Oral presentation (general), 日本薬学会

  • ポリコーム抑制複合体2機能低下型骨髄異形成症候群のがん幹細胞維持機構の解明と新規治療標的分子の探索

    青山和正 (口頭)

    第3回 化学及血清療法研究所 助成研究報告会 (熊本) , 

    2024.03
    , 

    Oral presentation (invited, special), 化学及血清療法研究所

  • レパトア特異性を活用したシングルセルRNAシークエンスが明らかにする多発性骨髄腫の不均一性(Single-Cell RNA Sequencing with Repertoire Clonality Reveals the Heterogeneity of Multiple Myeloma)

    神谷 高博, 大島 基彦, 小出 周平, 中島 やえ子, 青山 和正, 糸川 直樹, 山下 真幸, 土岐 典子, 片岡 圭亮, 岩間 厚志

    International Journal of Myeloma, 

    2023.05
    , 

    (一社)日本骨髄腫学会

  • Utx欠損によるクロマチンおよびトランスクリプトームリモデリングはマウスの骨髄腫様疾患を誘発する(Chromatin and transcriptomic remodeling by Utx loss and BrafV600E mutation induces myeloma-like disease in mice)

    Rizq Ola, 三村 尚也, 小出 周平, 柴宮 明日香, 宮本 友莉恵[長井], Rizk Mohamed, 大島 基彦, 百瀬 修二, 中島 やえ子, 青山 和正, 更屋 敦則, 堺田 惠美子, 中世古 知昭, 田丸 淳一, 本田 浩章, 岩間 厚志

    International Journal of Myeloma, 

    2023.05
    , 

    (一社)日本骨髄腫学会

  • PRC2の機能低下は、Cdkn2aの脱抑制を介して骨髄異形成症候群におけるp53依存性赤血球産生異常を誘発する

    青山 和正, 篠田 大輔, 鈴木 瑛美, 中島 やえ子, 大島 基彦, 小出 周平, Ola Rizq, 太良 史郎, 指田 吾郎, 岩間 厚志

    日本生化学会大会プログラム・講演要旨集, 

    2021.11
    , 

    (公社)日本生化学会

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Identification of Drug Targets for EZH2 Loss-of-Function Myelodysplastic Syndromes

    2024.10
    -
    2026.08

    公益信託日本白血病研究基金, 研究助成事業（高久史磨賞）, Principal investigator

  • EZH2 機能喪失型の骨髄異形成症候群に対する新規創薬標的分子

    2024.09
    -
    2025.03

    公益信託日本白血病研究基金, 2024年度日本血液学会研究助成, Principal investigator

  • "残存H3K27me3"を標的とするEZH2 機能低下型MDS に対する創薬研究

    2024.04
    -
    2025.03

    慶應義塾大学, 福澤基金研究補助, Principal investigator

  • パラダイムシフトをもたらすポリコーム抑制複合体の新規制御機構と創薬研究

    2024.04
    -
    2025.03

    慶應義塾大学, 学事振興資金による研究補助(個人研究) , Principal investigator

  • PRC2機能低下型MDSのがん幹細胞維持機構の解明と新規創薬標的の探索

    2023.04
    -
    2026.03

    日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

    　View Summary

    EZH1あるいはEZH2を酵素サブユニットとするポリコーム抑制複合体2は、抑制性のヒストン修飾であるH3K27me3を修飾することで遺伝子発現を制御するタンパク質の複合体である。EZH2の機能低下が、前白血病である骨髄異形成症候群(MDS)において高頻度に認められる。申請者らはEZH1による「残存H3K27me3」が、EZH2機能低下型MDSの維持に必須であることを明らかにした。しかし、「残存H3K27me3」に関する詳細な分子機構は明らかではなく、有効な治療法も確立されていない。本研究では、「残存H3K27me3」の維持を担うタンパク質を同定することで、MDSの新規創薬標的を見出す。

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Awards 【 Display / hide 】

  • 高久史磨賞

    青山和正, 2024.08, 公益信託日本白血病研究基金, Identification of Drug Targets for EZH2 Loss-of-Function Myelodysplastic Syndromes

    Type of Award： Award from publisher, newspaper, foundation, etc.

  • 第12回 次世代を担う若手ファーマ・バイオフォーラム2013 優秀発表賞受賞

    2013.09, 日本薬学会生物系薬学部会, c-Abl によるヒストン脱アセチル化を介したクロマチン構造変換と核内 F-アクチン形成

    Type of Award： Award from Japanese society, conference, symposium, etc.

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (HYGIENIC CHEMISTRY)

    2024

  • SEMINAR: (HYGIENIC CHEMISTRY)

    2024

  • RESEARCH FOR BACHELOR'S THESIS 1

    2024

  • PHARMACEUTICAL-ENGLISH SEMINAR

    2024

  • HYGIENIC CHEMISTRY AND PUBLIC HEALTH LABORATORY COURSE

    2024

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Educational Activities and Special Notes 【 Display / hide 】

  • ファカルティ・ディベロップメント（FD）参加 慶應義塾大学薬学部主催 内容“Study Abroad!! - To go, or not to go, that’s a question”

    2024.07

  • 学生実務実習 薬局訪問 コスモファーマシー (埼玉県新座市)

    2024.06

  • 学生実務実習 薬局訪問 富士見台調剤薬局 (東京都国立市)

    2024.06

  • ファカルティ・ディベロップメント（FD）参加(動画視聴) 慶應義塾主催 内容「生成AIについて」

    2024.05

  • 2024年度 慶應大学薬学部 学生実習委員

    2024.04
    -
    2025.03

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Academic Activities 【 Display / hide 】

  • 研究成果発表会採点委員 49th IMSUT (The Institute of Medical Science, the University of Tokyo) Founding Commemorative Symposium Flash Talks

    (東京大学医科学研究所 (Virtual)) , 

    2022.05

  • ポスター発表審査員Postbac Poster Day 2021 at National Institutes of Health(NIH)

    (National Institutes of Health (Virtual)) , 

    2021.04

  • ポスター発表審査員Postbac Poster Day 2020 at National Institutes of Health(NIH)

    (National Institutes of Health (Virtual)) , 

    2020.04

  • ポスター発表審査員Postbac Poster Day 2019 at National Institutes of Health(NIH)

    (National Institutes of Health(Bethesda, Maryland, USA)) , 

    2019.05

  • シンポジウムのオーガナイザー・司会 “Reproductive system and disease, Cancer epigenome, Public Symposium 2017”

    (千葉) , 

    2017.09

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Memberships in Academic Societies 【 Display / hide 】

  • 日本血液学会, 

    2022.03
    -
    Present

  • 日本生化学会, 

    2015.07
    -
    Present

  • 日本薬学会, 

    2010.12
    -
    Present
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