Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation
Open accessAbstract
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.
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Leukemia cells rely on SMARCA4 to support their oncogenic transcriptional program.
“A study found that leukemia cells rely on SMARCA4 to support their oncogenic transcriptional program [165].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [165]
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- Authors
- Shi, J., Whyte, W. A., Zepeda-Mendoza, C. J., Milazzo, J. P., Shen, C., Roe, J.-S., Minder, J. L., Mercan, F., Wang, E., Eckersley-Maslin, M. A., Campbell, A. E., Kawaoka, S., Shareef, S., Zhu, Z., Kendall, J., Muhar, M., Haslinger, C., Yu, M., Roeder, R. G., Wigler, M. H., Blobel, G. A., Zuber, J., Spector, D. L., Young, R. A., & Vakoc, C. R.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Whitehead Institute for Biomedical Research (US)
- Children's Hospital of Philadelphia (US)
- Research Institute of Molecular Pathology (AT)
- Boehringer Ingelheim (Austria) (AT)
- Rockefeller University (US)
- Corresponding author
- Vakoc, Christopher R.
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-11-27
- Volume
- 27
- Issue
- 24
- Pages
- 2648-2662
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3877755
- OpenAlex
- W2148261329
- Cited by
- 463
- References
- 58
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 29 · 2023: 36 · 2022: 40 · 2021: 61 · 2020: 43 · 2019: 35 · 2018: 37 · 2017: 41 · 2016: 38 · 2015: 42 · 2014: 20 · 2013: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- F. M. Kirby Foundation
- V Foundation for Cancer Research
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Leukemia and Lymphoma Society
- Edward P. Evans Foundation
- Wellcome Trust
- James N. Kirby Foundation
- National Institutes of Health
- U.S. Public Health Service (42694)
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (CA455087, NCI RO1 CA174793, R01CA174793, P01CA013106)
- National Institute of General Medical Sciences (R01GM042694, 42694)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK058044)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- SWI/SNF complex, SMARCA4, acute myeloid leukemia, MYC regulation, BRD4, leukemia maintenance, self-renewal, distal enhancers, focal amplification, transcriptional coactivator, oncogenic transcriptional programs
- MeSH terms
- DNA Helicases, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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