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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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HEMATOPOIESIS AND STEM CELLS

Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog Mll5

Vikas Madan1, Babita Madan1, Urszula Brykczynska2, Frédéric Zilbermann2, Kevin Hogeveen3, Konstanze Döhner4, Hartmut Döhner4, Odile Weber1, Carmen Blum1, Hans-Reimer Rodewald1, Paolo Sassone-Corsi3, Antoine H. F. M. Peters2, and Hans Jörg Fehling1

1 Institute of Immunology, University Clinics Ulm, Ulm, Germany; 2 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; 3 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg-Illkirch, France; and 4 Department of Internal Medicine III, University Clinics Ulm, Ulm, Germany

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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Related Article in Blood Online:

MLL5 governs hematopoiesis: a step closer
Han Liu, Todd D. Westergard, and James J.-D. Hsieh
Blood 2009 113: 1395-1396. [Full Text] [PDF]



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