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

Madan, Vikas and Madan, Babita and Brykczynska, Urszula and Zilbermann, Frederic and Hogeveen, Kevin and Doehner, Konstanze and Doehner, Hartmut and Weber, Odile and Blum, Carmen and Rodewald, Hans-Reimer and Sassone-Corsi, Paolo and 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

Abstract

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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author's personal web site or On departmental web site
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Date Deposited: 14 Dec 2009 13:50
Last Modified: 31 Jan 2013 01:01
URI: https://oak.novartis.com/id/eprint/975

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