Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains
- Jennifer J. Trowbridge1,
- Amit U. Sinha1,
- Nan Zhu1,
- Mingjie Li1,
- Scott A. Armstrong1 and
- Stuart H. Orkin1,2,3
- 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA
Abstract
Epigenetic mechanisms regulating leukemia stem cells (LSCs) are an attractive target for therapy of blood cancers. Here, we report that conditional knockout of the DNA methyltransferase Dnmt1 blocked development of leukemia, and haploinsufficiency of Dnmt1 was sufficient to delay progression of leukemogenesis and impair LSC self-renewal without altering normal hematopoiesis. Haploinsufficiency of Dnmt1 resulted in tumor suppressor gene derepression associated with reduced DNA methylation and bivalent chromatin marks. These results suggest that LSCs depend on not only active expression of leukemogenic programs, but also DNA methylation-mediated silencing of bivalent domains to enforce transcriptional repression.
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Footnotes
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↵3 Corresponding author.
E-mail orkin{at}bloodgroup.tch.harvard.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.184341.111.
- Received November 28, 2011.
- Accepted January 13, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press