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

Junwei Shi, Warren A. Whyte, Cinthya J. Zepeda-Mendoza, Joseph P. Milazzo, Chen Shen, Jae-Seok Roe, Jessica L. Minder, Fatih Mercan, Eric Wang, Melanie A. Eckersley-Maslin, Amy E. Campbell, Shinpei Kawaoka, Sarah Shareef, Zhu Zhu, Jude Kendall, Matthias Muhar, Christian Haslinger, Ming Yu, Robert G. Roeder, Michael H. Wigler & 5 others Gerd A. Blobel, Johannes Zuber, David L. Spector, Richard A. Young, Christopher R. Vakoc

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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.

Original languageEnglish
Pages (from-to)2648-2662
Number of pages15
JournalGenes and Development
Volume27
Issue number24
DOIs
Publication statusPublished - 2013 Dec 15

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Leukemia
Maintenance
Chromatin
Neoplasms
Chromatin Assembly and Disassembly
Acute Myeloid Leukemia
Adenosine Triphosphatases
Transcription Factors
Phenotype
Gene Expression
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Cite this

Shi, J., Whyte, W. A., Zepeda-Mendoza, C. J., Milazzo, J. P., Shen, C., Roe, J-S., ... Vakoc, C. R. (2013). Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes and Development, 27(24), 2648-2662. https://doi.org/10.1101/gad.232710.113
Shi, Junwei ; Whyte, Warren A. ; Zepeda-Mendoza, Cinthya J. ; Milazzo, Joseph P. ; Shen, Chen ; Roe, Jae-Seok ; Minder, Jessica L. ; Mercan, Fatih ; Wang, Eric ; Eckersley-Maslin, Melanie A. ; Campbell, Amy E. ; Kawaoka, Shinpei ; Shareef, Sarah ; Zhu, Zhu ; Kendall, Jude ; Muhar, Matthias ; Haslinger, Christian ; Yu, Ming ; Roeder, Robert G. ; Wigler, Michael H. ; Blobel, Gerd A. ; Zuber, Johannes ; Spector, David L. ; Young, Richard A. ; Vakoc, Christopher R. / Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. In: Genes and Development. 2013 ; Vol. 27, No. 24. pp. 2648-2662.
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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.",
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Shi, J, Whyte, WA, Zepeda-Mendoza, CJ, Milazzo, JP, Shen, C, Roe, J-S, Minder, JL, Mercan, F, Wang, E, Eckersley-Maslin, MA, Campbell, AE, Kawaoka, S, Shareef, S, Zhu, Z, Kendall, J, Muhar, M, Haslinger, C, Yu, M, Roeder, RG, Wigler, MH, Blobel, GA, Zuber, J, Spector, DL, Young, RA & Vakoc, CR 2013, 'Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation', Genes and Development, vol. 27, no. 24, pp. 2648-2662. https://doi.org/10.1101/gad.232710.113

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. / Shi, Junwei; Whyte, Warren A.; Zepeda-Mendoza, Cinthya J.; Milazzo, Joseph P.; Shen, Chen; Roe, Jae-Seok; Minder, Jessica L.; Mercan, Fatih; Wang, Eric; Eckersley-Maslin, Melanie A.; Campbell, Amy E.; Kawaoka, Shinpei; Shareef, Sarah; Zhu, Zhu; Kendall, Jude; Muhar, Matthias; Haslinger, Christian; Yu, Ming; Roeder, Robert G.; Wigler, Michael H.; Blobel, Gerd A.; Zuber, Johannes; Spector, David L.; Young, Richard A.; Vakoc, Christopher R.

In: Genes and Development, Vol. 27, No. 24, 15.12.2013, p. 2648-2662.

Research output: Contribution to journalArticle

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T1 - Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

AU - Shi, Junwei

AU - Whyte, Warren A.

AU - Zepeda-Mendoza, Cinthya J.

AU - Milazzo, Joseph P.

AU - Shen, Chen

AU - Roe, Jae-Seok

AU - Minder, Jessica L.

AU - Mercan, Fatih

AU - Wang, Eric

AU - Eckersley-Maslin, Melanie A.

AU - Campbell, Amy E.

AU - Kawaoka, Shinpei

AU - Shareef, Sarah

AU - Zhu, Zhu

AU - Kendall, Jude

AU - Muhar, Matthias

AU - Haslinger, Christian

AU - Yu, Ming

AU - Roeder, Robert G.

AU - Wigler, Michael H.

AU - Blobel, Gerd A.

AU - Zuber, Johannes

AU - Spector, David L.

AU - Young, Richard A.

AU - Vakoc, Christopher R.

PY - 2013/12/15

Y1 - 2013/12/15

N2 - 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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