2018 Fiscal Year Final Research Report
Molecular pathogenesis of bone marrow failure elucidated by comprehensive sequencing.
| Project/Area Number |
16H05338
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Research Collaborator |
YOSHIDA Kenichi
KON Ayana
KATAOKA Keisuke
ONO Kinji
KOSEKI Haruhiko
Miyazaki Yasushi
Chiba Shigeru
Nakao Shinji
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 骨髄不全症候群 / 再生不良性貧血 / 発作性夜間血色素尿症 / 骨髄異形成症候群 / 遺伝子変異 / コピー数異常 / 遺伝子発現異常 / 二次性白血病 |
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| Outline of Final Research Achievements |
In this study, we clarified novel pathogenesis of bone marrow hypoplasia and luekemia evolustion in cases with bone marrow failure syndromes by simultaneous genome and transcriptome analysis.
Genomic and RNA sequencing in the same case revealed that novel mutations, copy number alterations, and abnormal gene expression were significantly associated with pathophysiology of bone marrow failure syndromes. For example, gene expression and its associated mutations defined new classification of bone marrow failures into different groups such as stem cell and erythroid phenoytpes, which were related to clinical course of leukemia evolution. In addition, novel SAMD9/SAMD9L mutations and chromosome 7 deletions were coincidently identified in secondary myelodysplastic syndromes after congenital bone marrow failure. These findings were validated by analysis using basic animal models and clinical information on prognosis and morphological phenotype.
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| Free Research Field |
血液疾患におけるゲノム解析
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| Academic Significance and Societal Importance of the Research Achievements |
骨髄不全症候群は、骨髄異形成症候群、再生不良性貧血、発作性夜間血色素尿症を含む、骨髄造血機能の障害を共通の病態とする難治性疾患である。これらの疾患は、共通の遺伝子異常を呈しながらも、疾患特異的な異常をも来たすことが明らかとなっていた。これらの研究成果を踏まえ、本研究では、骨髄不全症候群おいてどのような異常がゲノム上あるいは遺伝子発現パターンに起こり、より悪性度の高い難治性の病型に変化するのか、さらに白血病への変化を引き起こすのかについて、これまでに培ったシーケンス技術と、マウスモデルを用いた機能解析によって明らかにした。
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