Biological characterization of DDX41 germline and somatic mutations in myeloid neoplasms

• Project/Area Number: 16K19574
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kyoto 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: ¥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.

Research Products

• [Journal Article] A novel genetic and morphologic phenotype of ARID2-mediated myelodysplasia (2018)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PhysiologicalSrsf2P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice (2017)
  • 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
  • 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
  • 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
  • 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
• [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
• [Presentation] Biological roles and potential therapeutic targeting of spliceosome mutations in myelodysplasia (2016)
  • Author(s): Ayana Kon, Seishi Ogawa
  • Organizer: The 75st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Kanagawa, Japan
  • Invited
• [Presentation] The biological characterization of Srsf2 P95H mutation in the pathogenesis of myelodysplasia (2016)
  • 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