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Tumor suppressor role of BCOR in hematopoiesis

Research Project

Project/Area Number 16K15498
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Hematology
Research InstitutionChiba University

Principal Investigator

Iwama Atsushi  千葉大学, 大学院医学研究院, 教授 (70244126)

Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsBCOR / がん抑制遺伝子 / 造血腫瘍 / Bcor / 急性リンパ芽球せい白血病 / 急性Tリンパ芽球性白血病 / ポリコーム群複合体 / 造血器腫瘍
Outline of Final Research Achievements

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR). We herein generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain (BcorΔE4/y). BcorΔE4/y thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL) mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly upregulated in BcorΔE4/y T-ALL cells. ChIP-seq analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a similar manner to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

Report

(3 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • Research Products

    (10 results)

All 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (5 results) (of which Int'l Joint Research: 1 results,  Invited: 5 results)

  • [Int'l Joint Research] Minnesota大学(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Cornell University(米国)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies2017

    • Author(s)
      Tanaka Tomoyuki、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Tara Shiro、Oshima Motohiko、Saraya Atsunori、Koide Shuhei、Si Sha、Manabe Ichiro、Sanada Masashi、Nakayama Manabu、Masuko Masayoshi、Sone Hirohito、Koseki Haruhiko、Iwama Atsushi
    • Journal Title

      The Journal of Experimental Medicine

      Volume: 214 Issue: 10 Pages: 2901-2913

    • DOI

      10.1084/jem.20170167

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia.2017

    • Author(s)
      Seki M, Kimura S, Isobe T, Yoshida K, (13 authors), Masuda K, Kawamoto H, Ohki K, Kato M, Arakawa Y, Koh K, Hanada R, Moritake H, Akiyama M, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi Y, Takagi M, Manabe A, Ohara A, Horibe K, Sanada M, Iwama A, Mano H, Miyano S, Ogawa S, Takita J
    • Journal Title

      Nature Genetics

      Volume: 49 Issue: 8 Pages: 1274-1281

    • DOI

      10.1038/ng.3900

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Polycomb repressive complexes in hematological malignancies.2017

    • Author(s)
      Iwama A
    • Journal Title

      Blood

      Volume: 130 Issue: 1 Pages: 23-29

    • DOI

      10.1182/blood-2017-02-739490

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Ineffective erythropoiesis in myelodysplastic syndrome2017

    • Author(s)
      岩間厚志
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 造血器腫瘍とエピジェネティクス2017

    • Author(s)
      岩間厚志
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ポリコーム群複合体による造血幹細胞のエピジェネティック制御2017

    • Author(s)
      岩間厚志
    • Organizer
      第65回 日本輸血・細胞治療学会総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 造血幹細胞のエピジェネティック制御2017

    • Author(s)
      岩間厚志
    • Organizer
      第27回 日本サイトメトリー学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Polycomb repressive complexes in hematological malignancies2016

    • Author(s)
      Iwama A
    • Organizer
      11th International Workshop on Melecular aspects of myeloid stem cell development and leukemia
    • Place of Presentation
      Cincinnati Children’s Hospital Medical Center,Ohio,U.S.A.
    • Year and Date
      2016-05-02
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2016-04-21   Modified: 2022-06-07  

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