An MLL-dependent Network Sustains Hematopoiesis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Jun 8

PMID 23744037

Citations 50

Authors

Erika L Artinger

Bibhu P Mishra

Kristin M Zaffuto

Bin E Li

Elaine K Y Chung

Adrian W Moore

Yufei Chen

Chao Cheng

Patricia Ernst

Affiliations

Soon will be listed here.

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.

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