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The mechanism of leukemic transformation from myeloproliferative neoplasms

Research Project

Project/Area Number 21K08399
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionFukushima Medical University

Principal Investigator

Ueda Koki  福島県立医科大学, 医学部, 講師 (80632190)

Co-Investigator(Kenkyū-buntansha) 池田 和彦  福島県立医科大学, 医学部, 教授 (90381392)
三村 耕作  福島県立医科大学, 医学部, 准教授 (90568031)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords骨髄増殖性腫瘍 / 急性転化 / 急性骨髄性白血病 / CALR / EZH2 / JAK2 / ASXL1 / MDMX
Outline of Research at the Start

本邦において年間5000から6000人が新規に発症するMPNは、比較的高率にAMLに転化することが知られており、転化を認めた場合の予後は不良である。p53抑制因子であるMDMXは急性転化をきたした症例で高頻度に遺伝子増幅がみられることが報告されている。申請者らは、白血病発症においてMDMXのp53依存性・非依存性機能が重要な役割を果たしていることを、Mdmxトランスジェニックマウスモデルを用いて明らかにしてきた。このマウスをMPNモデルマウスと交配し、MPNからAMLへと進行する急性転化モデルを樹立する。さらに、MDMX阻害剤を用いて、急性転化を阻止する治療モデルを確立する。

Outline of Final Research Achievements

To elucidate critical factors to induce leukemic transformation from myeloproliferative neoplasms (MPN), we generated a murine model which slowly develop acute myeloid leukemia (AML) from moderate phenotypes of MPN. We crossbred Calr-10d mice with Ezh2-KO mice, and obtained Calr-10d, Ezh2-KO, Calr-10d;Ezh2-KO respectively. We observed these mice, and found that only Calr-10d;Ezh2-KO mice died with AML or severe MPN during age 10 to 18 months. Calr-10d and Ezh2-KO mice lived nearly 24 months.Upregulation of polycomb target genes were observed in hematopoietic stem cells (HSCs) of Calr-10d;Ezh2-KO mice.Presently, we are analyzing HSCs of moribund AML and MPN mice, and we are expecting to detect important factors for leukemic transformation.

Academic Significance and Societal Importance of the Research Achievements

骨髄増殖性腫瘍の治療は進歩していますが、白血病への進行を阻止する方法は確立していません。造血細胞にどのような変化が起きると白血病に進行するのかを明らかにするためには、患者さんの骨髄を頻回に採取して、白血病に進行した患者さんと進行しなかった患者さんの違いを調べるのが一番ですが、それでは患者さんの負担が大きすぎます。今回の研究成果から、マウスを用いて病態解明を進めることが期待できます。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (9 results)

All 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 3 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Impaired Repopulating Ability of Uhrf2?/? Hematopoietic Progenitor Cells in Mice2023

    • Author(s)
      Sano Takahiro、Ueda Koki、Minakawa Keiji、Mori Tsutomu、Hashimoto Yuko、Koseki Haruhiko、Takeishi Yasuchika、Ikeda Kazuhiko、Ikezoe Takayuki
    • Journal Title

      Genes

      Volume: 14 Issue: 8 Pages: 1531-1531

    • DOI

      10.3390/genes14081531

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Review: MDMX plays a central role in leukemic transformation and may be a promising target for leukemia prevention strategies2023

    • Author(s)
      Ueda Koki
    • Journal Title

      Experimental Hematology

      Volume: in press Pages: 10-18

    • DOI

      10.1016/j.exphem.2023.04.001

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Gaining MOMENTUM against anaemic myelofibrosis2023

    • Author(s)
      Ikeda Kazuhiko、Ueda Koki
    • Journal Title

      The Lancet

      Volume: 401 Issue: 10373 Pages: 248-249

    • DOI

      10.1016/s0140-6736(23)00171-x

    • Related Report
      2022 Research-status Report
  • [Journal Article] Comparison of cryoprotectants in hematopoietic cell infusion?related adverse events2022

    • Author(s)
      Ikeda Kazuhiko、Minakawa Keiji、Yamahara Kenichi、Yamada‐Fujiwara Minami、Okuyama Yoshiki、Fujiwara Shin‐ichiro、Yamazaki Rie、Kanamori Heiwa、Iseki Tohru、Nagamura‐Inoue Tokiko、Kameda Kazuaki、Nagai Kazuhiro、Fujii Nobuharu、Ashida Takashi、Hirose Asao、Takahashi Tsutomu、Ohto Hitoshi、Ueda Koki、Tanosaki Ryuji
    • Journal Title

      Transfusion

      Volume: Epub Issue: 6 Pages: 1280-1288

    • DOI

      10.1111/trf.16877

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism2021

    • Author(s)
      Ueda Koki,Kumari Rajni,Schwenger Emily,Wheat Justin et al.
    • Journal Title

      Cancer Cell

      Volume: 39 Issue: 4 Pages: 529-547

    • DOI

      10.1016/j.ccell.2021.02.006

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice.2021

    • Author(s)
      Minakawa K, Yokokawa T, Ueda K, Nakajima O, Misaka T, Kimishima Y, Wada K, Tomita Y, Miura S, Sato Y, Mimura K, Sugimoto K, Nakazato K, Nollet KE, Ogawa K, Ikezoe T, Hashimoto Y, Takeishi Y, Ikeda K.
    • Journal Title

      J Hematol Oncol.

      Volume: 14 Issue: 1 Pages: 52-52

    • DOI

      10.1186/s13045-021-01064-8

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils2021

    • Author(s)
      Kimishima Yusuke、Misaka Tomofumi、Yokokawa Tetsuro、Wada Kento、Ueda Koki、Sugimoto Koichi、Minakawa Keiji、Nakazato Kazuhiko、Ishida Takafumi、Oshima Motohiko、Koide Shuhei、Shide Kotaro、Shimoda Kazuya、Iwama Atsushi、Ikeda Kazuhiko、Takeishi Yasuchika
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6177-6177

    • DOI

      10.1038/s41467-021-26435-0

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epigenetic Achilles’ heel of AML2021

    • Author(s)
      Ueda Koki、Steidl Ulrich
    • Journal Title

      Nature Cancer

      Volume: 2 Issue: 5 Pages: 481-483

    • DOI

      10.1038/s43018-021-00212-w

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Interaction between JAK2-Mutated Neutrophils and Platelets Initiates Thrombosis Via Neutrophil Extracellular Traps2023

    • Author(s)
      Koki Ueda, Saori Miura, Tomofumi Misaka, Keiji Minakawa, Yuka Sato, Yasuchika Takeishi, Kazuhiko Ikeda
    • Organizer
      The 65th American Society of Hematology (ASH) Annual meeting and Exposition
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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