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Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12000-5. doi: 10.1073/pnas.1301278110. Epub 2013 Jun 6.

An MLL-dependent network sustains hematopoiesis.

Author information

1
Department of Genetics , Institute for Quantitative Biomedical Sciences, and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.

Abstract

The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll-dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll-dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll-deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia.

KEYWORDS:

HSC; epigenetics; proliferation

PMID:
23744037
PMCID:
PMC3718146
DOI:
10.1073/pnas.1301278110
[Indexed for MEDLINE]
Free PMC Article

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