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Molecular analysis of pediatric acute megakaryoblastic leukemia without Down syndrome

Research Project

Project/Area Number 20K08157
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionJichi Medical University (2021-2023)
Okayama University (2020)

Principal Investigator

SHIMADA AKIRA  自治医科大学, 医学部, 教授 (70391836)

Co-Investigator(Kenkyū-buntansha) 林 泰秀  群馬県衛生環境研究所, 研究企画係, 研究員 (30238133)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsAMKL / JAK阻害剤 / 次世代シーケンサー解析 / drug repositioning / JAK/STAT阻害剤 / HSP90阻害剤 / SMAC mimetics / 薬剤耐性 / 非アポトーシス性細胞死 / 白血病幹細胞 / RBM15-MKL1キメラ遺伝子 / 急性巨核芽球性白血病 / 再発 / 次世代シーケンサー / 薬剤感受性 / 小児 / 分子標的薬
Outline of Research at the Start

急性巨核芽球性白血病(Acute megakaryoblastic leukemia, AMKL, FAB分類 M7)は全AMLの1%とされるが、小児AMLでは約15%を占め、非ダウン症のAMKLはこれまで一般的に予後不良とされていたが、最近の研究ではキメラ遺伝子によって予後が異なることが明らかとなってきた。今回我々は初発と再発AMKLの遺伝子変化を次世代シーケンサーで解析し、再発に伴うクローン進化を明らかとする。また新規薬剤を含む各種薬剤感受性について検討することで、予後不良なAMKLに対する臨床応用にむけた新規分子標的薬探索を行う予定である。

Outline of Final Research Achievements

Gene panel analysis of 10 AMKL specimens revealed various gene mutations such as KIT, SPI1, GATA1, NCOR2, SETBP1, CSF3R, etc., but no commonality, suggesting a heterogenous disease.
We investigated the effects of novel agents in AMKL cell lines and found that JAK inhibitors were promising, so we investigated the impact of cytarabine and JAK inhibitors in six AMKL cell lines. In our 3D co-culture system with mesenchymal cells that mimics the bone marrow microenvironment, synergistic effects were observed in two cell lines, MOLM16 and MKPL1, and these two cell lines are now being tested in transplantation experiments in mice.

Academic Significance and Societal Importance of the Research Achievements

非ダウン症の急性巨核芽球性白血病(AMKL)は予後不良であるが、遺伝子パネル解析から、変異は個々の症例で異なっていた。AMKL細胞株6種類でcytarabineとJAK阻害剤の効果について検討したところ、MOLM16とMKPL1の2種類の細胞株でシナジー効果を見られたため、この2株についてマウスの移植実験で検証中である。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (10 results)

All 2024 2023 2022 2021 2020

All Journal Article (10 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 10 results,  Open Access: 5 results)

  • [Journal Article] Cytokine profiling in 128 patients with transient abnormal myelopoiesis: a report from the JPLSG TAM-10 trial2024

    • Author(s)
      Yamato Genki、Tsumura Yusuke、Muramatsu Hideki、Shimada Akira、Imaizumi Takahiro、Tsukagoshi Hiroyuki、Kaburagi Taeko、Shiba Norio、Yamada Yoshiyuki、Deguchi Takao、Kawai Tomoko、Terui Kiminori、Ito Etsuro、Watanabe Kenichiro、Hayashi Yasuhide
    • Journal Title

      Blood Advances

      Volume: in press Issue: 12 Pages: 3120-3129

    • DOI

      10.1182/bloodadvances.2023011628

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High <i>IL2RA</i>/CD25 expression is a prognostic stem cell biomarker for pediatric acute myeloid leukemia without a core‐binding factor2023

    • Author(s)
      Aoki Takahiro、Shiba Norio、Tsujimoto Shinichi、Yamato Genki、Hara Yusuke、Kato Shota、Yoshida Kenichi、Ogawa Seishi、Hayashi Yasuhide、Iwamoto Shotaro、Taki Tomohiko、Shimada Akira、Iijima‐Yamashita Yuka、Horibe Keizo、Tawa Akio、Taga Takashi、Adachi Souichi、Tomizawa Daisuke
    • Journal Title

      Pediatric Blood &amp; Cancer

      Volume: 71 Issue: 2

    • DOI

      10.1002/pbc.30803

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TP53 and RB1 alterations characterize poor prognostic subgroups in pediatric acute myeloid leukemia.2023

    • Author(s)
      Hara Y, Shiba N, Yoshida K, Yamato G, Kaburagi T, Shiraishi Y, Ohki K, Shiozawa Y, Kawamura M, Kawasaki H, Sotomatsu M, Takizawa T, Matsuo H, Shimada A, Kiyokawa N, Tomizawa D, Taga T, Ito E, Horibe K, Miyano S, Adachi S, Taki T, Ogawa S, Hayashi Y.
    • Journal Title

      Genes Chromosomes Cancer

      Volume: 62 Issue: 7 Pages: 412-422

    • DOI

      10.1002/gcc.23147

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genome-wide DNA Methylation Analysis in Pediatric Acute Myeloid Leukemia.2022

    • Author(s)
      Yamato G, Kawai T, Shiba N, Ikeda J, Hara Y, Ohki K, Tsujimoto SI, Kaburagi T, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Taga T, Horibe K, Ogawa S, Hata K, Hayashi Y.
    • Journal Title

      Blood advances

      Volume: in press Issue: 11 Pages: 3207-3219

    • DOI

      10.1182/bloodadvances.2021005381

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Investigation of the molecular causes underlying physical abnormalities in Diamond‐Blackfan anemia patients with RPL5 haploinsufficiency2021

    • Author(s)
      Fukui Yuko、Hayano Satoru、Kawanabe Noriaki、Wang Ziyi、Shimada Akira、Saito Megumu K.、Asaka Isao、Kamioka Hiroshi
    • Journal Title

      Pathology International

      Volume: 71 Issue: 12 Pages: 803-813

    • DOI

      10.1111/pin.13168

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Correction to: Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome.2021

    • Author(s)
      Taga T, Tanaka S, Hasegawa D, Terui K, Toki T, Iwamoto S, Hiramatsu H, Miyamura T, Hashii Y, Moritake H, Nakayama H, Takahashi H, Shimada A, Taki T, Ito E, Hama A, Ito M, Koh K, Hasegawa D, Saito AM, Adachi S, Tomizawa D.
    • Journal Title

      Leukemia

      Volume: 35 Issue: 12 Pages: 2508-2516

    • DOI

      10.1038/s41375-021-01397-w

    • NAID

      120007150319

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.2021

    • Author(s)
      Kaburagi T, Yamato G, Shiba N, Yoshida K, Hara Y, Tabuchi K, Shiraishi Y,Ohki K, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Taki T, Kiyokawa N, Tomizawa D, Horibe K, Miyano S, Taga T, Adachi S, Ogawa S, Hayashi Y.
    • Journal Title

      Haematologica

      Volume: - Issue: 3 Pages: 583-592

    • DOI

      10.3324/haematol.2020.269431

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The outcomes of relapsed acute myeloid leukemia in children: Results from the Japanese Pediatric Leukemia/Lymphoma Study Group AML‐05R study.2020

    • Author(s)
      Moritake H, Tanaka S, Miyamura T, Nakayama H, Shiba N, Shimada A, Terui K, Yuza Y, Koh K, Goto H, Kakuda H, Saito A, Hasegawa D, Iwamoto S, Taga T, Adachi S, Tomizawa D.
    • Journal Title

      Pediatric Blood & Cancer

      Volume: 68 Issue: 1

    • DOI

      10.1002/pbc.28736

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Attempts to optimize postinduction treatment in childhood acute myeloid leukemia without core-binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).2020

    • Author(s)
      Hasegawa D, Tawa A, Tomizawa D, Watanabe T, Saito AM, Kudo K, Taga T, Iwamoto S, Shimada A, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Goto H, Kosaka Y, Miyachi H, Horibe K, Nakahata T, Adachi S.
    • Journal Title

      Pediatric Blood and Cancer

      Volume: 67 Issue: 12

    • DOI

      10.1002/pbc.28692

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Panel-based next-generation sequencing facilitates the characterization of childhood acute myeloid leukemia in clinical settings2020

    • Author(s)
      Ishida H, Iguchi A, Aoe M, Nishiuchi R, Matsubara T, Keino D, Sanada M, Shimada A
    • Journal Title

      Biomedical Reports

      Volume: 10 Issue: 5 Pages: 14859-14859

    • DOI

      10.3892/br.2020.1353

    • NAID

      120006956811

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research

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Published: 2020-04-28   Modified: 2025-01-30  

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