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MLL5 contributes to hematopoietic stem cell fitness and homeostasis.

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.

Pubmed ID: 18818388

Authors

  • Zhang Y
  • Wong J
  • Klinger M
  • Tran MT
  • Shannon KM
  • Killeen N

Journal

Blood

Publication Data

February 12, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA40046
  • Agency: NCI NIH HHS, Id: CA84221

Mesh Terms

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