Elucidation of 3D genome alteration and chronic inflammatory effects associated with the acquisition of mutations in leukemia development

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16306
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kumamoto University
• Principal Investigator: Kawai Mayu (徳舛麻友) 熊本大学, 国際先端医学研究機構, 特定事業研究員 (50942687)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: クロマチン高次構造 / 急性骨髄性白血病 / 染色体異常

Outline of Final Research Achievements

3D genome organization is a fundamental feature of genome interactions and influences transcriptional regulation. Genetic and chromosomal abnormalities are the main cause of leukemia, and it is not fully understood if these abnormalities affect 3D genome organization. To understand this correlation, we investigated genome-wide chromatin looping in the mouse model of acute myeloid leukemia (AML) with inversion of chromosome 16, inv(16). Our observations showed enhanced chromatin loops in the leukemia cells. Notably, CBFβ-SMMHC oncoprotein produced in inv(16)AML and its binding partner, RUNX1, colocalized at most of the loop anchors. Our leukemia model provides evidence that oncogenic transcriptional machinery greatly influences the looping structure, leading to leukemia-specific gene expression.

Free Research Field

白血病

Academic Significance and Societal Importance of the Research Achievements

本研究により、inv(16)AML特有の染色体異常から生成されるオンコプロテインが、異常転写因子複合体の形成を経て、転写という機能面のみならず、クロマチン高次構造の変化も引き起こすことが明らかとなった。この高次構造変化は白血病特異的遺伝子発現の調節に関与していることが示唆され、新たな白血病化機序の解明につながると期待できる。さらに、この異常転写因子複合体の形成に関与するエピジェネティック制御因子を同定することで、疾患特異的新規治療法の開発へと進展することが期待できる。