MLL5 contributes to hematopoietic stem cell fitness and homeostasis

Blood. 2009 Feb 12;113(7):1455-63. doi: 10.1182/blood-2008-05-159905. Epub 2008 Sep 25.

Abstract

MLL5 is a novel trithorax group gene and a candidate tumor suppressor gene located within a 2.5-Mb interval of chromosome band 7q22 that frequently is deleted in human myeloid malignancy. Here we show that inactivation of the Mll5 gene in mice results in a 30% reduction in the average representation of hematopoietic stem cells and in functional impairment of long-term hematopoietic repopulation potential under competitive conditions. Bone marrow cells from Mll5-deficient mice were defective in spleen colony-forming assays, and the mutant mice showed enhanced susceptibility to 5-fluorouracil-induced myelosuppression. Heterozygous and homozygous Mll5 mutant mice did not spontaneously develop hematologic cancers, and loss of Mll5 did not alter the phenotype of a fatal myeloproliferative disorder induced by oncogenic Kras in vivo. Collectively, the data reveal an important role for Mll5 in HSC homeostasis and provide a basis for further studies to explore its role in leukemogenesis.

Publication types

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

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / toxicity
  • Apoptosis / drug effects
  • Bone Marrow Transplantation
  • Cell Cycle / drug effects
  • Cell Differentiation / physiology
  • Fluorouracil / toxicity
  • Gene Expression / physiology
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Homeostasis / physiology*
  • Integrases / genetics
  • Leukemia / genetics
  • Leukemia / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / drug effects
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Spleen / cytology

Substances

  • Antimetabolites, Antineoplastic
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • MLL5 protein, mouse
  • Cre recombinase
  • Integrases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Fluorouracil