Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia

Abstract

Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myeloid leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared to other lineages. This result was striking in comparison to data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes including MYC, a well-established target of BRG1 activity in AML. Overall, small molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes. Our studies reveal the breadth of SWI/SNF dependency and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.

RNA Polymerase II, the BAF remodeler and transcription factors synergize to evict nucleosomes

“…These include oncogenic fusion of the BAF subunit SS18 with an SSX protein in synovial sarcoma and interaction of BAF with EWS-FLI1 in Ewing sarcoma causing aberrant BAF complex targeting 74,75 , subunit overexpression 76 , and heterozygous missense mutations within the Brg1 subunit gene in diverse cancers, several of which were characterized as gain-of-function for remodeling activity 77 . Furthermore, genetic dependency on Brg1 observed in several cancers has led to the emergence of pharmacological inhibition of the BRG1 ATPase activity as a novel therapeutic strategy 78–80 . Our study explains how BAF can synergize with cell-type-specific chromatin regulators and TFs, shedding light into how BAF functions may be hijacked in cancers.…”