An MLL-dependent network sustains hematopoiesis

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin Immunoprecipitation
  • Epigenesis, Genetic / physiology*
  • Gene Regulatory Networks / physiology*
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / physiology*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Models, Biological
  • Myeloid-Lymphoid Leukemia Protein / physiology*
  • Proto-Oncogene Proteins / physiology


  • KMT2A protein, human
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase

Associated data

  • GEO/GSE47205