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PML-RARA of the short but long isoform initiate from TIM-3+ leukemic stem cells with hierarchical leukemic organization

Research Project

Project/Area Number 22K19544
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
Research InstitutionKanazawa University

Principal Investigator

Miyamoto Toshihiro  金沢大学, 医学系, 教授 (70343324)

Co-Investigator(Kenkyū-buntansha) 菊繁 吉謙  九州大学, 大学病院, 講師 (40619706)
Project Period (FY) 2022-06-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
KeywordsAPL / 白血病幹細胞 / PML::RARA / 急性前骨髄球性白血病 / PML-RARA
Outline of Research at the Start

未だ白血病幹細胞の存在が否定的なAPLにおいて、我々が同定した白血病幹細胞機能分子TIM-3を指標として幹細胞集団を細分画することで、APL幹細胞の存在を実証する。さらにAPL特異的PML-RARA遺伝子は染色体転座切断部位により2つに大別されshort typeとlong typeにおいて異なる白血化機構を解明し、より有効な標的治療を開発する。

Outline of Final Research Achievements

LSC of AML can be enriched in CD34+CD38- fraction and reconstitute human AML in vivo. However, in APL, which constitutes 10% of all AML and is driven by PML::RARA fusion genes, the presence of LSC has long been unidentified because of difficulty in reconstitution of APL. We show that LSC of short-type isoform APL, defined by different breakpoints of PML, concentrate in CD34+CD38- fraction and express TIM-3. Short-type APL exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types. CD34+CD38-TIM-3+ short-type APL efficiently reconstituted APL in xenograft with high penetration, whereas CD34- differentiated APL cells did not. CD34+CD38-TIM-3+ short-type APL reconstituted APL after serial transplantation. Identification of LSC in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding APL leukemogenesis and devise individual treatments for eradication of APL LSC.

Academic Significance and Societal Importance of the Research Achievements

APLは異種移植系で安定して白血病を再構築可能な白血病幹細胞分画は報告されておらず、本研究が初めてAPL幹細胞の存在を明らかにした。また同一のPML::RARA融合遺伝子であってもゲノム切断部位で違うshort-typeとlong-typeで、初めて異なる白血化機構を解明した独自性の高い研究である。従来、APLはPML::RARA融合遺伝子獲得のみの単純な発症様式と考えられていたが、多様性に富む白血病である可能性を示した。今後は2つのタイプの白血化機構の相違を明らかにし、各病型に特化した標的治療が開発できれば、新規APL標的治療としてブレイクスルーとなる。

Report

(2 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (7 results)

All 2022 2021

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (2 results) (of which Invited: 2 results)

  • [Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022

    • Author(s)
      Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
    • Journal Title

      Blood Adv.

      Volume: 6 Issue: 7 Pages: 2388-2402

    • DOI

      10.1182/bloodadvances.2021004618

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Real-world treatment patterns and clinical outcomes in patients with AML unfit for first-line intensive chemotherapy.2022

    • Author(s)
      Miyamoto T, Sanford D, Tomuleasa C, Hsiao HH, Olivera LJE, Enjeti AK, Gimenez Conca A, Castillo TBD, Girshova L, Martelli MP, Guvenc B, Delgado A, Duan Y, Garbayo Guijarro B, Llamas C, Lee JH.
    • Journal Title

      Leuk Lymph

      Volume: 63 Issue: 4 Pages: 928-938

    • DOI

      10.1080/10428194.2021.2002321

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TET2 Clonal Hematopoiesis Is Associated With Anthracycline-Induced Cardiotoxicity in Patients With Lymphoma2022

    • Author(s)
      Hatakeyama Kiwamu、Hieda Michinari、Semba Yuichiro、Moriyama Shohei、Wang Yuqing、Maeda Takahiro、Kato Koji、Miyamoto Toshihiro、Akashi Koichi、Kikushige Yoshikane
    • Journal Title

      JACC: CardioOncology

      Volume: 4 Issue: 1 Pages: 141-143

    • DOI

      10.1016/j.jaccao.2022.01.098

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan2022

    • Author(s)
      Ikezoe T, Ando K, Onozawa M, Yamane T, Hosono N, Morita Y, Kiguchi T, Iwasaki H, Miyamoto T, Matsubara K, Sugimoto S, Miyazaki Y, Kizaki M, Akashi K.
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 12 Pages: 4258-4266

    • DOI

      10.1111/cas.15458

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Circulating CD34+?cells of primary myelofibrosis patients contribute to myeloid-dominant hematopoiesis and bone marrow fibrosis in immunodeficient mice2021

    • Author(s)
      Saito Noriyuki、Yamauchi Takuji、Kawano Noriaki、Ono Rintaro、Yoshida Shuro、Miyamoto Toshihiro、Kamimura Tomohiko、Shultz Leonard D.、Saito Yoriko、Takenaka Katsuto、Shimoda Kazuya、Harada Mine、Akashi Koichi、Ishikawa Fumihiko
    • Journal Title

      International Journal of Hematology

      Volume: 115 Issue: 2 Pages: 198-207

    • DOI

      10.1007/s12185-021-03239-y

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] クローン性造血に潜む内科併存疾患2022

    • Author(s)
      宮本敏浩
    • Organizer
      第86回日本内科学会北陸支部生涯教育講演会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 急性骨髄性白血病の新規治療2022

    • Author(s)
      宮本敏浩
    • Organizer
      第22回日本薬学会Pharmoco-Hematologyシンポジウム
    • Related Report
      2022 Research-status Report
    • Invited

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Published: 2022-07-05   Modified: 2025-01-30  

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