Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia
- Matthew G. Guenther1,
- Lee N. Lawton1,
- Tatiana Rozovskaia2,
- Garrett M. Frampton1,3,
- Stuart S. Levine1,
- Thomas L. Volkert1,
- Carlo M. Croce4,
- Tatsuya Nakamura4,
- Eli Canaani2, and
- Richard A. Young1,3,5
- 1 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
- 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
- 3 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 4 Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA
Abstract
Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.
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Footnotes
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↵5 Corresponding author.
↵5 E-MAIL young{at}wi.mit.edu; FAX (617) 258-0367.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1741408.
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- Received September 16, 2008.
- Accepted November 4, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
