Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation.
Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in ∼3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.
['Shi|Junwei|J|', 'Whyte|Warren A|WA|', 'Zepeda-Mendoza|Cinthya J|CJ|', 'Milazzo|Joseph P|JP|', 'Shen|Chen|C|', 'Roe|Jae-Seok|JS|', 'Minder|Jessica L|JL|', 'Mercan|Fatih|F|', 'Wang|Eric|E|', 'Eckersley-Maslin|Melanie A|MA|', 'Campbell|Amy E|AE|', 'Kawaoka|Shinpei|S|', 'Shareef|Sarah|S|', 'Zhu|Zhu|Z|', 'Kendall|Jude|J|', 'Muhar|Matthias|M|', 'Haslinger|Christian|C|', 'Yu|Ming|M|', 'Roeder|Robert G|RG|', 'Wigler|Michael H|MH|', 'Blobel|Gerd A|GA|', 'Zuber|Johannes|J|', 'Spector|David L|DL|', 'Young|Richard A|RA|', 'Vakoc|Christopher R|CR|']
D045744:Cell Line, Tumor D049109:Cell Proliferation D004265:DNA Helicases D004268:DNA-Binding Proteins D004742:Enhancer Elements, Genetic D015972:Gene Expression Regulation, Neoplastic D055785:Gene Knockdown Techniques D006801:Humans D015470:Leukemia, Myeloid, Acute D009687:Nuclear Proteins D011401:Promoter Regions, Genetic D011485:Protein Binding D016271:Proto-Oncogene Proteins c-myc D014157:Transcription Factors
SWI/SNF leukemia Myc Brg1 enhancer Brd4