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

• Published in: Blood Vol. 113; no. 7; pp. 1444 - 1454
• Main Authors: Madan, Vikas, Madan, Babita, Brykczynska, Urszula, Zilbermann, Frédéric, Hogeveen, Kevin, Döhner, Konstanze, Döhner, Hartmut, Weber, Odile, Blum, Carmen, Rodewald, Hans-Reimer, Sassone-Corsi, Paolo, Peters, Antoine H.F.M., Fehling, Hans Jörg
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2009; American Society of Hematology
• Subjects: Animals; Cell Differentiation - immunology; Cellular Biology; Female; Genes, Lethal; Growth Disorders - genetics; Growth Disorders - immunology; Hematopoiesis - immunology; Hematopoietic Stem Cells - cytology; Heterozygote; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Infertility, Male - genetics; Infertility, Male - immunology; Life Sciences; Lymphocytes - cytology; Male; Mice; Mice, Knockout; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Phenotype; Pregnancy; Radiation Tolerance - genetics
• ISSN: 0006-4971; 1528-0020
• 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.