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Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5.

Authors: Madan, V  Madan, B  Brykczynska, U  Zilbermann, F  Hogeveen, K  Dohner, K  Dohner, H  Weber, O  Blum, C  Rodewald, HR  Sassone-Corsi, P  Peters, AH  Fehling, HJ 
Citation: Madan V, etal., Blood. 2009 Feb 12;113(7):1444-54. doi: 10.1182/blood-2008-02-142638. Epub 2008 Oct 24.
Pubmed: (View Article at PubMed) PMID:18952892
DOI: Full-text: DOI:10.1182/blood-2008-02-142638

The human Mixed-Lineage-Leukemia-5 (MLL5) gene is located in a genomic region frequently deleted in patients with myeloid malignancies and encodes a widely expressed nuclear protein most closely related to MLL1, a Trithorax transcriptional regulator with established involvement in leukemogenesis. Although the physiologic function of MLL5 is completely unknown, domain structure and homology to transcriptional regulators with histone methyltransferase activity suggest a role in epigenetic gene regulation. To investigate physiologic functions of Mll5, we have generated a knockout mouse mutant using Cre/loxP technology. Adult homozygous Mll5-deficient mice are obtained at reduced frequency because of postnatal lethality. Surviving animals display a variety of abnormalities, including male infertility, retarded growth, and defects in multiple hematopoietic lineages. Interestingly, Mll5(-/-) mice die of sublethal whole-body irradiation but can be rescued with wild-type bone marrow grafts. Flow cytometric ana-lysis, bone marrow reconstitution, and in vivo BrdU-labeling experiments reveal numerical, functional, and cell-cycle defects in the lineage-negative Sca-1(+), Kit(+) (LSK) population, which contains short- and long-term hematopoietic stem cells. Together, these in vivo findings establish several nonredundant functions for Mll5, including an essential role in regulating proliferation and functional integrity of hematopoietic stem/progenitor cells.

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CRRD Object Information
CRRD ID: 9588548
Created: 2014-10-30
Species: All species
Last Modified: 2014-10-30
Status: ACTIVE



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