Elucidating the molecular mechanisms underlying the clonal evolution of leukemic stem cells

• Project/Area Number: 18K16084
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto University
• Principal Investigator: Kon Ayana 京都大学, 医学研究科, 助教 (20772403)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄異形成症候群 / 急性骨髄性白血病 / クローン進化 / RCAS/TVAシステム / マウスモデル / スプライシング因子 / 白血病幹細胞

Outline of Final Research Achievements

Next-generation sequencing technology have revealed a comprehensive registry of driver mutations recurrently found in MDS patients. It has also been revealed that driver mutations are acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis. To understand the molecular mechanisms underlying the clonal evolution of founding clones, we generated two leukemic mice models, including MLL/AF9 driven leukemic mice models and pre-leukemic mice models using RCAS/TVA mediated gene transfer. By exome sequencing of serial BM samples of these mice models, we clarified the detailed clonal architecture over time. Further, we performed genome-wide screens using CRISPR/Cas9 technology to identify novel candidate genes that are essential for splicing factor mutated cells to be clonally selected. Findings from this study are expected to contribute significantly to the advance of understandings of MDS.

Academic Significance and Societal Importance of the Research Achievements

骨髄異形成症候群(MDS)および急性骨髄性白血病は、加齢に伴い造血幹細胞に遺伝子変異が蓄積して発症する腫瘍性疾患であり、高齢化に伴い患者数が増加している。造血幹細胞が複数の変異を獲得し、クローン選択によって高度な多様性をもった細胞集団が形成される分子メカニズムについては、発症の本質に関わる問題であるにもかかわらず、なお多くが不明である。本研究成果は、治療抵抗性のがんであるMDSの複雑な分子病態を明らかにしたもので、将来的には、難治性がんの治療成績向上に資する可能性がある意義深い研究成果と考えている。

Research Products

• [Journal Article] Clonal evolution of myelodysplastic syndromes (2020)
  • Author(s): Ayana Kon
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 4 Pages: 358-367
  • DOI: 10.11406/rinketsu.61.358
  • NAID: 130007839413
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes (2020)
  • Author(s): Ochi Y, Ogawa Seishi., et al.
  • Journal Title: Cancer Discov Volume: - Issue: 6 Pages: 836-853
  • DOI: 10.1158/2159-8290.cd-19-0982
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clonal evolution of myeloid malignancies (2020)
  • Author(s): Ayana Kon
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 9 Pages: 1120-1129
  • DOI: 10.11406/rinketsu.61.1120
  • NAID: 130007937122
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Myelodysplastic Syndrome-Associated SRSF2 Mutations Cause Splicing Changes by Altering Binding Motif Sequences (2019)
  • Author(s): Masaki So、Ikeda Shun、Hata Asuka、Shiozawa Yusuke、Kon Ayana、Ogawa Seishi、Suzuki Kenji、Hakuno Fumihiko、Takahashi Shin-Ichiro、Kataoka Naoyuki
  • Journal Title: Frontiers in Genetics Volume: 10 Pages: 1-8
  • DOI: 10.3389/fgene.2019.00338
  • Peer Reviewed / Open Access
• [Journal Article] Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis (2019)
  • Author(s): Kakiuchi Nobuyuki et al.
  • Journal Title: Nature Volume: 577 Issue: 7789 Pages: 260-265
  • DOI: 10.1038/s41586-019-1856-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular pathogenesis of disease progression in MLL-rearranged AML. (2018)
  • Author(s): Kotani S, Yoda A, Kon A, Kataoka K, Ochi Y, Shiozawa Y, Hirsch C, Takeda J, Ueno H, Yoshizato T, Yoshida K, Nakagawa MM, Nannya Y, Kakiuchi N, Yamauchi T, Aoki K, Shiraishi Y, Miyano S, Maeda T, Maciejewski JP, Takaori-Kondo A, Ogawa S, Makishima H.
  • Journal Title: Leukemia Volume: 33 Issue: 3 Pages: 612-624
  • DOI: 10.1038/s41375-018-0253-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The functional role of compound DDX41 germline and somatic R525H mutations in the development of myeloid neoplasms (2020)
  • Author(s): Kon A, Nakagawa MM, Inagaki R, Kataoka K, Ochi Y, Makishima H, Nakayama M, Koseki H, Nannya Y, Ogawa S
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] The functional characterization of compound DDX41 germline and somatic R525H mutations in the development of myeloid malignancies (2020)
  • Author(s): Kon A, Nakagawa MM, Inagaki R, Kataoka K, Ochi Y, Makishima H, Nakayama M, Koseki H, Nannya Y, Ogawa S
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Functional characterization of compound DDX41 germline and somatic R525H mutations in the development of myeloid malignancies (2020)
  • Author(s): Kon A, Nakagawa MM, Inagaki R, Kataoka K, Ochi Y, Makishima H, Nakayama M, Koseki H, Nannya Y, Ogawa S
  • Organizer: 62nd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Biological characterization of the U2af1 S34F mutation in the pathogenesis of myelodysplasia (2019)
  • Author(s): Ayana Kon, Yasuhito Nannya, Keisuke Kataoka, Manabu Nakayama, Haruhiko Koseki, Masashi Sanada, Hideki Makishima, Marshall Masahiro Nakagawa, Seishi Ogawa
  • Organizer: 24th Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] The role of compound DDX41 germline and somatic mutations in myeloid neoplasms (2019)
  • Author(s): Ayana Kon, Masahiro Marshall Nakagawa, Yasuhito Nannya, Keisuke Kataoka, Yotaro Ochi, June Takeda, Kenichi Yoshida, Manabu Nakayama, Haruhiko Koseki, Hideki Makishima, Seishi Ogawa
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] STAG2 mutations alter epigenic and transcriptional dynamics in myeloid neoplasms. (2019)
  • Author(s): Ayana Kon
  • Organizer: Meeting of Leukemic and Hematopoietic Stem Cells in Tokyo
  • Invited
• [Presentation] スプライシング因子変異による骨髄異形成症候群発症の分子病態の解明 (2018)
  • Author(s): Ayana Kon
  • Organizer: 日本癌学会総会
• [Presentation] Functional analysis of DDX41 germline and somatic mutations in myeloid neoplasms. (2018)
  • Author(s): Ayana Kon, June Takeda, Keisuke Kataoka, Kenichi Yoshida, Masahiro Marshall Nakagawa, Tetsuichi Yoshizato, Manabu Nakayama, Haruhiko Koseki, Hideki Makishima, Seishi Ogawa
  • Organizer: 日本癌学会総会
• [Presentation] Functional analysis of DDX41 germline and somatic mutations in myeloid neoplasms. (2018)
  • Author(s): Ayana Kon, June Takeda, Keisuke Kataoka, Kenichi Yoshida, Masahiro Marshall Nakagawa, Tetsuichi Yoshizato, Manabu Nakayama, Haruhiko Koseki, Hideki Makishima, Seishi Ogawa
  • Organizer: 日本血液学会学術集会
• [Presentation] Biological characterization of the U2af1 S34F mutation in the pathogenesis of myelodysplasia (2018)
  • Author(s): Ayana Kon, Yasuhito Nannya, Marshall Masahiro Nakagawa, Keisuke Kataoka, Masashi Sanada, Manabu Nakayama, Haruhiko Koseki, Seishi Ogawa
  • Organizer: 60th ASH Annual Meeting
  • Int'l Joint Research