Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance.
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.
Institute for Research in Immunology and Cancer, Montreal, QC, Canada;
Manuel
M
Buscarlet
Veneta
V
Krasteva
Lena
L
Ho
Camille
C
Simon
Josée
J
Hébert
Brian
B
Wilhelm
Gerald R
GR
Crabtree
Guy
G
Sauvageau
Pierre
P
Thibault
Julie A
JA
Lessard
D000818:Animals; D015139:Blotting, Southern; D042002:Chromatin Assembly and Disassembly; D002853:Chromatography, Liquid; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
D009687:Nuclear Proteins; D012333:RNA, Messenger; C084011:SMARCA2 protein, human; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases