title: Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation.
abstract: 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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Junwei
authors.initials: J
authors.lastname: Shi
authors.forename: Warren A
authors.initials: WA
authors.lastname: Whyte
authors.forename: Cinthya J
authors.initials: CJ
authors.lastname: Zepeda-Mendoza
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Milazzo
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.forename: Jae-Seok
authors.initials: JS
authors.lastname: Roe
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Minder
authors.forename: Fatih
authors.initials: F
authors.lastname: Mercan
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Eckersley-Maslin
authors.forename: Amy E
authors.initials: AE
authors.lastname: Campbell
authors.forename: Shinpei
authors.initials: S
authors.lastname: Kawaoka
authors.forename: Sarah
authors.initials: S
authors.lastname: Shareef
authors.forename: Zhu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.forename: Matthias
authors.initials: M
authors.lastname: Muhar
authors.forename: Christian
authors.initials: C
authors.lastname: Haslinger
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Michael H
authors.initials: MH
authors.lastname: Wigler
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: David L
authors.initials: DL
authors.lastname: Spector
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C499336:SMARCA1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Brd4; Brg1; Myc; SWI/SNF; enhancer; leukemia