Chronological analysis of clonal architecture in myelodysplastic syndromes
Project/Area Number |
17H04990
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Research Category |
Grant-in-Aid for Young Scientists (A)
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Allocation Type | Single-year Grants |
Research Field |
Tumor biology
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Research Institution | Kyoto University |
Principal Investigator |
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Project Period (FY) |
2017-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥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)
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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).
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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。
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Report
(3 results)
Research Products
(9 results)
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[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.
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Journal Title
Leukemia
Volume: 33
Issue: 3
Pages: 612-624
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Nat. Commun.
Volume: 9
Issue: 1
Pages: 3649-3649
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Leukemia
Volume: 32(3)
Issue: 3
Pages: 839-843
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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