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Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance.

Buscarlet M, Krasteva V, Ho L, Simon C, Hébert J, Wilhelm B, Crabtree GR, Sauvageau G, Thibault P, Lessard JA

Institute for Research in Immunology and Cancer, Montreal, QC, Canada;

In mammals, combinatorial assembly of alternative families of subunits confers functional specificity to adenosine triphosphate (ATP)-dependent SWI/SNF-like Brg/Brm-associated factor (BAF) chromatin remodeling complexes by creating distinct polymorphic surfaces for interaction with regulatory elements and DNA-binding factors. Although redundant in terms of biochemical activity, the core ATPase subunits, BRG/SMARCA4 and BRM/SMARCA2, are functionally distinct and may contribute to complex specificity. Here we show using quantitative proteomics that BAF complexes expressed in leukemia are specifically assembled around the BRG ATPase. Moreover, using a mouse model of acute myeloid leukemia, we demonstrate that BRG is essential for leukemia maintenance, as leukemic cells lacking BRG rapidly undergo cell-cycle arrest and apoptosis. Most importantly, we show that BRG is dispensable for the maintenance of immunophenotypic long-term repopulating hematopoietic stem cells, suggesting that adroit targeting of BRG in leukemia may have potent and specific therapeutic effects.

Blood 2014;123(11):1720-8.

Pubmed ID: 24478402

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