运行x1
染色质
生物
白血病
细胞生物学
细胞生长
癌症研究
转录因子
增强子
遗传学
造血
干细胞
基因
作者
Kazunari Aoki,Mizuki Hyuga,Yusuke Tarumoto,Gohei Nishibuchi,Atsushi Ueda,Yotaro Ochi,Shinya Sugino,Takashi Mikami,Hirokazu Kobushi,Ikunoshin Kato,Koshi Akahane,Takeshi Inukai,Akifumi Takaori‐Kondo,Junko Takita,Seishi Ogawa,Kosuke Yusa
出处
期刊:Blood
[American Society of Hematology]
日期:2023-11-03
被引量:1
标识
DOI:10.1182/blood.2023020857
摘要
Acute leukemia cells require bone marrow microenvironments, termed niches, which provide leukemic cells with niche factors that are essential for leukemic cell survival and/or proliferation. However, it remains unclear how the dynamics of the leukemic cell-niche interaction are regulated. Using a genome-wide CRISPR screen, we discovered that canonical BRG1/BRM-associated factor (cBAF), a variant of the switch/sucrose non-fermenting chromatin remodeling complex, regulates migratory response of human T-cell acute lymphoblastic leukemia (T-ALL) cells to a niche factor CXCL12. Mechanistically, cBAF maintains chromatin accessibility and allows RUNX1 to bind to CXCR4 enhancer regions. cBAF inhibition evicts RUNX1 from the genome, resulting in CXCR4 downregulation and impaired migration activity. In addition, cBAF maintains chromatin accessibility preferentially at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CDK6; therefore, cBAF inhibition negatively impacts cell proliferation and profoundly induces apoptosis. This anticancer effect was also confirmed using T-ALL xenograft models, suggesting cBAF as a promising therapeutic target. Thus, we provide novel evidence that cBAF regulates the RUNX1-driven leukemic program and governs migration activity toward CXCL12 and cell-autonomous growth in human T-ALL.
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