2018 Fiscal Year Final Research Report
Functional analysis of causative genes identified by comprehensive genetic analysis
| Project/Area Number |
16K10032
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | University of Miyazaki |
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Principal Investigator |
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| Research Collaborator |
Morishita Kazuhiro
Koga Yuhki
Watanabe Hiroyoshi
Tsuji Shoji
Morishita shinichi
Takagi Masatoshi
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 白血病 / 小児 / ETV6遺伝子 / 生殖細胞変異 / 家族性 / エクソーム解析 |
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| Outline of Final Research Achievements |
We performed comprehensive genetic analyses on five families in which at least two children developed acute leukemia among all of their relatives. Exome sequencing identified the same ETV6 germline mutations in the siblings with acute lymphoblastic leukemia in one family. ETV6 is a transcriptional repressor. We analyzed the subcellular localization, transcriptional activity, and colony formation assay using novel ETV6 mutation-transformed cells; however, we failed to detect a significant difference compared with wild-type cells. In addition, novel ETV6 mutation-transformed hematopoietic stem cells were transplanted to immunocompromised mice; however, no significant differences in peripheral blood components, including white blood cell differentiation, after engraftment were observed between wild-type and mutated-type cells. In conclusion, the novel ETV6 mutation identified in our family did not have any effect on lymphoid differentiation linked to leukomogenesis or thrombocytopenia.
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| Free Research Field |
小児血液・腫瘍
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| Academic Significance and Societal Importance of the Research Achievements |
米国のMoriyamaらの報告では、4,405例の小児ALL患者でETV6遺伝子のターゲットシーケンスが施行され35症例に生殖細胞変異を見出しその頻度は約1%とされる（Lancet Oncology, 2015）。ETV6生殖細胞変異は他のがん種においてもがん化に関与していることが想定されるため、小児ALL患者におけるETV6生殖細胞変異患者のスクリーニングの必要性、治療方針および治療終了後のフォローアップ法の確立が重要である。ただし、今回のようにデータベースでは一塩基多型として扱われていないが表原型を示さない変異も含まれている可能性があり、機能解析をとおして適切な判断が重要である。
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