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

Madan, Vikas, Madan, Babita, Brykczynska, Urszula, Zilbermann, Frederic, Hogeveen, Kevin, Doehner, Konstanze, Doehner, Hartmut, Weber, Odile, Blum, Carmen, Rodewald, Hans-Reimer, Sassone-Corsi, Paolo, Peters, Antoine and Fehling, Hans Joerg (2009) Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5. Blood, 113 (7). pp. 1444-1454. ISSN 1528-0020


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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Date Deposited: 14 Dec 2009 13:50
Last Modified: 31 Jan 2013 01:01