Investigation of molecular mechanism of new recurrent fusion genes in ALL

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02835
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nagoya University
• Principal Investigator: Hayakawa Fumihiko 名古屋大学, 医学系研究科(保健), 教授 (30402580)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 急性リンパ性白血病 / MEF2D / ZNF384 / 薬剤スクリーニング / マイクロRNA / スタウロスポリン

Outline of Final Research Achievements

In the present study, we clarified molecular mechanisms of leukemia development by MEF2D-fusion gene and ZNF384-fusion gene, new recurrent gene abnormalities of acute lymphoblastic leukemia. MEF2D fusion gene evaded from the inhibition by miRNA, which caused higher expression of MEF2D fusion protein than wild-type MEF2D. Highly expressed MEF2D fusion protein inhibited the transcriptional activity of PAX5. We also revealed that ZNF384 fusion protein had stronger binding affinity to co-activator such as EP300 than wild-type, which lead to its stronger transcriptional activity. Furthermore, we performed drug screening to discover compounds that cause proteolysis of MEF2D-fusion protein. We found that staurosporine, a multi-kinase inhibitor, was a such drug and caused apoptosis of MEF2D-fusion gene positive ALL cell lines.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

MEF2D融合遺伝子、ZNF384融合遺伝子は最近発見され、白血病化機序など全く不明の遺伝子異常であるが、それぞれ、日本人成人急性リンパ性白血病の10%、20%程度を占める高頻度遺伝子異常である。このような白血病に関して、将来の治療薬開発のための標的となる分子が明らかにされたり、既存の化合物の中から治療薬となりうる化合物をスクリーニングする手法が開発されたことの意義は大きいと考えられる。