Chronological analysis of clonal architecture in myelodysplastic syndromes

• Project/Area Number: 17H04990
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: Kyoto University
• Principal Investigator: Yoshizato Tetsuichi 京都大学, 医学研究科, 助教 (70786392)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥24,440,000 (Direct Cost: ¥18,800,000、Indirect Cost: ¥5,640,000); Fiscal Year 2018: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2017: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
• Keywords: 骨髄異形成症候群 / ゲノム解析 / 遺伝子変異 / クローン構造 / 二次性白血病 / 継時的解析

Outline of Final Research Achievements

The purpose of this study was to identify the molecular markers of myelodysplastic syndromes through evaluating the chronological change of clonal architectures.
We found genetic abnormalities involving ARID2 in about 1% of cases and revealed its association with megakaryocyte dysplasia (Sakai H et al. Leukemia 2018). MLL/AF9 positive mouse leukemia cells were serially transplanted to mice by mimicking repeated recurrences. Through this experiment, we identified GNB2 mutation as a novel target (Kotani S et al. Leukemia 2019). In myelodysplastic syndromes, splicing factors are the most common targets of mutations. We comprehensively analyzed splicing abnormalities caused by splicing factor mutations and identified their targets (Shiozawa Y et al. Nat Com 2018). We revealed that cases with TP53 mutations, which is a well-known poor prognostic marker, showed a relatively good response to DNA methylation inhibitor Azacitidine, although this response was not durable (in preparation).

Academic Significance and Societal Importance of the Research Achievements

骨髄異形成症候群は高率に急性骨髄性白血病へ高率に移行する予後不良の血液腫瘍である。骨髄異形成症候群は高齢者に多く、今後高齢化社会の進行により発症率は上昇すると考えられ、予後を改善することは非常に重要である。本研究では、骨髄異形成症候群に生じているゲノム異常を様々な手法を用いて評価し、ARID2やGNB2などの新規標的遺伝子を多数同定した。また、TP53変異は非常に予後の悪い変異として知られているが、DNAメチル化阻害薬が一時的にはあるものの有効であることを明らかにした。DNAメチル化阻害薬投与後に同種造血幹細胞移植を実施することで予後が改善できる可能性が示唆される。

Research Products

• [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
• [Journal Article] Significance of somatic mutations on the prognosis of myelodysplastic syndromes (2018)
  • Author(s): Yoshizato T
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 8 Pages: 1078-1085
  • DOI: 10.11406/rinketsu.59.1078
  • NAID: 130007472195
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia. (2018)
  • Author(s): Shiozawa Y, Malcovati L, Gall A, Sato-Otsubo A, Kataoka K, Sato Y, Watatani Y, Suzuki H, Yoshizato T, Yoshida K, Sanada M, Makishima H, Shiraishi Y, Chiba K, Hellstrom-Lindberg E, Miyano S, Ogawa S, Cazzola M
  • Journal Title: Nat. Commun. Volume: 9 Issue: 1 Pages: 3649-3649
  • DOI: 10.1038/s41467-018-06063-x
  • NAID: 120006537149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] Impact of genetic alterations in stem cell transplantation for myelodysplastic syndromes (2018)
  • Author(s): Yoshizato T
  • Organizer: The 80th annual meeting of the Japanese society of hematology
  • Int'l Joint Research / Invited
• [Presentation] Somatic mutation in MDS and its effect on outcome (2017)
  • Author(s): Tetsuichi Yoshizato
  • Organizer: 第79回日本血液学会学術集会
  • Invited
• [Presentation] Impact of genetic abnormalities on outcome in patients with MDS after stem-cell transplantation. (2017)
  • Author(s): Tetsuichi Yoshizato
  • Organizer: The Nordic MDS Group (NMDSG) meeting 2017 autumn
  • Int'l Joint Research
• [Presentation] U2AF2 mutations in myelodysplastic syndromes (2017)
  • Author(s): Tetsuichi Yoshizato
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] U2AF2 mutations in myelodysplastic syndromes (2017)
  • Author(s): Tetsuichi Yoshizato
  • Organizer: 第76回日本癌学会 学術総会