Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Acute leukemia cells depend on bone marrow microenvironments (niches) for survival and proliferation.
• The precise regulation of leukemic cell-niche interactions remains incompletely understood.

Purpose of the Study:

• To elucidate the regulatory mechanisms governing leukemic cell-niche interactions.
• To identify novel therapeutic targets for T-cell acute lymphoblastic leukemia (T-ALL).

Main Methods:

• Genome-wide CRISPR screen to identify regulatory factors.
• Investigation of the canonical BRG1/BRM-associated factor (cBAF) complex's role.
• Analysis of chromatin accessibility, transcription factor binding (RUNX1), and gene expression (CXCR4, CDK6).
• Validation in T-ALL xenograft models.

Main Results:

• cBAF regulates the migration of T-ALL cells towards the niche factor CXCL12.
• cBAF maintains chromatin accessibility for RUNX1 binding to the CXCR4 enhancer, controlling migration.
• cBAF inhibition leads to RUNX1 eviction, CXCR4 downregulation, impaired migration, reduced proliferation (via CDK6), and increased apoptosis.
• Anticancer effects were confirmed in T-ALL xenograft models.

Conclusions:

• cBAF is a critical regulator of the RUNX1-driven leukemic program in T-ALL.
• cBAF governs T-ALL cell migration towards CXCL12 and cell-autonomous growth.
• cBAF inhibition demonstrates significant anticancer effects, positioning it as a promising therapeutic target for T-ALL.