The multistep molecular mechanism of acute megakaryoblastic leukemia in Down syndrome

2017 Fiscal Year Final Research Report

• Project/Area Number: 26253061
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hirosaki University
• Principal Investigator: Ito Etsuro 弘前大学, 医学研究科, 教授 (20168339)
• Co-Investigator(Kenkyū-buntansha): 照井 君典 弘前大学, 医学研究科, 准教授 (00333740) ; 土岐 力 弘前大学, 医学研究科, 講師 (50195731) ; 金崎 里香 弘前大学, 医学研究科, 助教 (60722882)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: 白血病 / ダウン症候群

Outline of Final Research Achievements

We performed functional study of Down syndrome associated acute megakaryocytic leukemia (DS-AMKL)-specific mutations to understand the mechanisms of multistep leukemogenesis in DS, and found the following results.
1）We found many novel recurrent mutations in DS-AMKL samples using whole exome sequencing, and performed functional study for these mutations.　2）We established the K562 subclones expressing GATA1s exclusively (GATA1s subclones) using CRISPR/Cas9 gene editing. GATA1s subclones expressed KIT at higher levels compared to the wild type K562. Engineered DNA-binding molecule-mediated ChIP (enChIP) sequencing and 3C-based proximity ligation assays revealed that in the GATA1s subclone, GATA1-binding region at -87 kb with respect to the transcription start site was more proximate to the KIT transcriptional start site compared to the wild type, suggesting that the N-terminal domain of GATA1 is essential for proper genomic conformation and gene expression regulation of KIT.

Free Research Field

小児血液学