急性白血病细胞需要骨髓微环境，称为生态位，它为白血病细胞提供对于白血病细胞存活和/或增殖至关重要的生态位因子。然而，目前尚不清楚白血病细胞-生态位相互作用的动态是如何调节的。使用全基因组 CRISPR 筛选，我们发现经典的 BRG1/BRM 相关因子 (cBAF)（开关/蔗糖非发酵染色质重塑复合物的一种变体）可调节人 T 细胞急性淋巴细胞白血病 (T- ALL）细胞对利基因子 CXCL12 的影响。从机制上讲，cBAF 维持染色质可及性并允许 RUNX1 与 CXCR4 增强子区域结合。 cBAF 抑制会将 RUNX1 从基因组中逐出，导致 CXCR4 下调并损害迁移活性。此外，cBAF优先在RUNX1结合位点维持染色质可及性，确保RUNX1在这些位点结合，并且是RUNX1调节基因（例如CDK6）表达所必需的；因此，cBAF 抑制会对细胞增殖产生负面影响并严重诱导细胞凋亡。 T-ALL 异种移植模型也证实了这种抗癌作用，表明 cBAF 作为一个有前途的治疗靶点。因此，我们提供了新的证据，表明 cBAF 调节 RUNX1 驱动的白血病程序，并控制人类 T-ALL 中向 CXCL12 的迁移活动和细胞自主生长。版权所有 © 2023 美国血液学会。

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.Copyright © 2023 American Society of Hematology.