Characterization of missense mutations in TET2 gene in leukemia

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K19206
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory medicine
• Research Institution: Chiba University (2017-2019); Doshisha University (2016)
• Principal Investigator: YAMAGATA Kazuyuki 千葉大学, 大学院医学研究院, 助教 (60455912)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: エピジェネティクス / TET2 / 白血病 / 体細胞変異 / 生化学 / EP4遺伝子

Outline of Final Research Achievements

Missense mutations in Ten-eleven translocation 2 (TET2) gene are frequently found in leukaemia patients. Although mutations span the entire coding region, they tend to cluster in the C-terminal enzymatic domain and a cysteine-rich (CR) domain of unknown function. Herein, we found the CR domain binds chromatin preferentially at the histone H3 tail by recognising H3 lysine 36 mono- and dimethylation (H3K36me1/2). Importantly, missense mutations in the CR domain perturbed TET2 recruitment to the target locus and its enzymatic activities. Our findings identify a novel H3K36me recognition domain and uncover a critical link between histone modification and DNA hydroxylation in leukaemogenesis.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

本研究は白血病で高頻度に体細胞変異の起こるTET2の機能未知ドメインがDNA配列変異を超えた意義(エピジェネティクス変異という)、すなわちヒストン修飾を読む機能を持つことを明らかにした。さらに体細胞変異がヒストン修飾の認識を変えることを示した。これらは学術的に興味深いのみならず、白血病に対する創薬について新しいターゲットを提示したという点で応用面でも重要である。