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Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev 2012 Feb 15;26(4):344-9

Date

02/22/2012

Pubmed ID

22345515

Pubmed Central ID

PMC3289882

DOI

10.1101/gad.184341.111

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.

Author List

Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SH

Author

Nan Zhu PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Chromatin
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Haploinsufficiency
Kaplan-Meier Estimate
Leukemia
Mice
Neoplastic Stem Cells
Tumor Suppressor Proteins
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc