Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

  1. Christopher R. Vakoc1,4,9
  1. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
  2. 2Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York 11794, USA;
  3. 3Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;
  4. 4Watson School of Biological Sciences, Cold Spring Harbor, New York 11724, USA;
  5. 5Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
  6. 6Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria;
  7. 7Boehringer Ingelheim Regional Center Vienna GmbH and Company KG, 1120 Vienna, Austria;
  8. 8Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA;

    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.

    Keywords

    Footnotes

    • Received October 11, 2013.
    • Accepted November 7, 2013.

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