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Biological characterization of DDX41 germline and somatic mutations in myeloid neoplasms

Research Project

Project/Area Number 16K19574
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Hematology
Research InstitutionKyoto University

Principal Investigator

Kon Ayana  京都大学, 医学研究科, 特定助教 (20772403)

Research Collaborator OGAWA Seishi  京都大学, 大学院医学研究科, 教授 (60292900)
KOSEKI Haruhiko  国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (40225446)
NAKAYAMA Manabu  公益財団法人かずさDNA研究所, 先端研究開発部, 主任研究員 (30370927)
Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords骨髄異形成症候群 / 急性骨髄性白血病 / 遺伝子改変マウス / 新規遺伝子変異 / DDX41 / マウスモデル / 遺伝子変異
Outline of Final Research Achievements

DDX41 is a newly identified leukemia predisposition gene encoding an RNA helicase, whose germline mutations are tightly associated with late-onset myeloid malignancies. In typical cases, a germline loss-of-function allele is compounded by a somatic missense mutation affecting the helicase domain in the remaining allele (p.R525H). To clarify the role of these DDX41 alleles, we generated Ddx41 heterozygous knock-out mice, as well as mice carrying the conditional R525H missense allele. In noncompetitive transplantation experiments, the recipient mice transplanted with Ddx41 R525H BM cells or Ddx41 heterozygous knock-out BM cells showed significant and progressive leukopenia compared with wild-type controls. Further, we identified several candidate targets of Ddx41 mutations through RNA sequencing of Ddx41 mutated hematopoietic stem and progenitor cells.

Report

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

    (8 results)

All 2018 2017 2016

All Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 4 results,  Acknowledgement Compliant: 1 results) Presentation (4 results) (of which Invited: 1 results)

  • [Journal Article] A novel genetic and morphologic phenotype of ARID2-mediated myelodysplasia2018

    • Author(s)
      Sakai H, Hosono N, Nakazawa H, Przychodzen B, Polprasert C, Carraway HE, Sekeres MA, Radivoyevitch T, Yoshida K, Sanada M, Yoshizato T, Kataoka K, Nakagawa MM, Ueno H, Nannya Y, Kon A, Shiozawa Y, Takeda J, Shiraishi Y, Chiba K, Miyano S, Singh J, Padgett RA, Ogawa S, Maciejewski JP, Makishima H
    • Journal Title

      Leukemia

      Volume: 32(3) Issue: 3 Pages: 839-843

    • DOI

      10.1038/leu.2017.319

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] PhysiologicalSrsf2P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice2017

    • Author(s)
      Kon Ayana、Yamazaki Satoshi、Nannya Yasuhito、Kataoka Keisuke、Ota Yasunori、Nakagawa Masahiro Marshall、Yoshida Kenichi、Shiozawa Yusuke、Morita Maiko、Yoshizato Tetsuichi、Sanada Masashi、Nakayama Manabu、Koseki Haruhiko、Nakauchi Hiromitsu、Ogawa Seishi
    • Journal Title

      Blood

      Volume: 131 Issue: 6 Pages: 621-635

    • DOI

      10.1182/blood-2017-01-762393

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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] Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms.2016

    • Author(s)
      Mori T, Nagata Y, Makishima H, Sanada M, Shiozawa Y, Kon A, Yoshizato T, Sato-Otsubo A, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Ishiyama K, Miyawaki S, Mori H, Nakamaki T, Kihara R, Kiyoi H, Koeffler HP, Shih LY, Miyano S, Naoe T, Haferlach C, Kern W, Haferlach T, Ogawa S, Yoshida K.
    • Journal Title

      Leukemia.

      Volume: 30 Issue: 11 Pages: 2270-2273

    • DOI

      10.1038/leu.2016.212

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Biological characterization of DDX41 germline and somatic mutations in myeloid neoplasms.2017

    • Author(s)
      Ayana Kon, Keisuke Kataoka, Hideki Makishima, June Takeda, Tetsuichi Yoshizato, Masahiro Nakagawa, Yasunori Kogure, Kenichi Yoshida, Manabu Nakayama, Haruhiko Koseki, Seishi Ogawa
    • Organizer
      日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Biological characterization of DDX41 germline and somatic mutations in myeloid neoplasms.2017

    • Author(s)
      Ayana Kon, Keisuke Kataoka, June Takeda, Tetsuichi Yoshizato, Masahiro Nakagawa, Yasunori Kogure, Kenichi Yoshida, Manabu Nakayama, Haruhiko Koseki, Hideki Makishima, Seishi Ogawa
    • Organizer
      日本癌学会総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Biological roles and potential therapeutic targeting of spliceosome mutations in myelodysplasia2016

    • Author(s)
      Ayana Kon, Seishi Ogawa
    • Organizer
      The 75st Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      Yokohama, Kanagawa, Japan
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] The biological characterization of Srsf2 P95H mutation in the pathogenesis of myelodysplasia2016

    • Author(s)
      Ayana Kon, Satoshi Yamazaki, Yusuke Shiozawa, Keisuke Kataoka, Yasunori Ota, Maiko Morita, Tetsuichi Yoshizato, Masashi Sanada, Kenichi Yoshida, Hideki Makisima, Yasuhito Nanya, Shinichi Kotani, June Takeda, Yosaku Watatani, Yotaro Ochi, Manabu Nakayama, Haruhiko Koseki, Hiromitsu Nakauchi, Seishi Ogawa
    • Organizer
      The 78th Annual Meeting of the Japanese Society of Hematology
    • Place of Presentation
      Yokohama, Kanagawa, Japan
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2019-03-29  

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