Functional redundancy of H3K4 methyltransferase family on epigenetic regulation in leukemia

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22399
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Chiba University
• Principal Investigator: Hoshii Takayuki 千葉大学, 大学院医学研究院, 講師 (20464042)
• Co-Investigator(Kenkyū-buntansha): 金田 篤志 千葉大学, 大学院医学研究院, 教授 (10313024)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: エピゲノム / 白血病 / 重複性 / 酵素ドメイン / H3K4メチル化

Outline of Final Research Achievements

MLL-rearrangement (MLL-r) is one of a poor prognostic factor in acute myeloid leukemia (AML). Histone H3K4 methylation, which is important in regulating gene expression, is increased in this type of leukemia cells. However, no single modifying enzyme for H3K4me has been identified and this suggests that the involvement of multiple enzymes. In this study, we identified the dependency against enzymatic domains on KMT2 family proteins in both human and mouse leukemia cell lines, then analyzed the possibility of overlapping regulation of enzymatic activity on KMT2 family proteins in MLL-r AML cells. The results of this study suggest that targeting multiple enzymatic activity on KMT2 family proteins may produce a synergistic effect on cell growth suppression and will provide a new therapeutic tool for cancer therapy.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

MLL再構成は小児性白血病で高頻度に認められる染色体転座であり、MLL再構成型急性骨髄性白血病は再発率が高く極めて予後が悪い。そのためMLL再構成型白血病の治療薬開発は急務と言える。MLL遺伝子自体がヒストンメチル化酵素であり、この白血病ではヒストンメチル化異常も報告されているが、その分子メカニズムは不明である。本研究結果はその一端を説明するものであり、この分子機構を標的とする治療法開発に有用であると期待される。