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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1444-1454.
Prepublished online as a Blood First Edition Paper on October 24, 2008; DOI 10.1182/blood-2008-02-142638.
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Submitted February 28, 2008
Accepted October 21, 2008
Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog Mll5
Vikas Madan, Babita Madan, Urszula Brykczynska, Frederic Zilbermann, Kevin Hogeveen, Konstanze Dohner, Hartmut Dohner, Odile Weber, Carmen Blum, Hans-Reimer Rodewald, Paolo Sassone-Corsi, Antoine H.F.M. Peters, and Hans Jorg Fehling*
Institute of Immunology, University Clinics Ulm, Ulm, Germany
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
Institut de Genetique et de Biologie Moleculaire et Cellulaire, Strasbourg, France
Department of Internal Medicine III, University Clinics Ulm, Ulm, Germany
* Corresponding author; email: joerg.fehling{at}uni-ulm.de.
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 physiological 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 physiological functions of Mll5, we have generated a knockout mouse mutant using Cre/loxP technology. Adult homozygous Mll5-deficient mice are obtained at reduced frequency due to post-natal lethality. Surviving animals display a variety of abnormalities, including male infertility, retarded growth and defects in multiple hematopoietic lineages. Interestingly, Mll5-/- mice succumb to sub-lethal whole-body irradiation, but can be rescued with wild-type bone marrow grafts. Flow cytometric analysis, 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 that contains short- and long-term hematopoietic stem cells. Together, these in vivo findings establish several non-redundant functions for Mll5 including an essential role in regulating proliferation and functional integrity of hematopoietic stem/progenitor cells.
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