期刊
BLOOD
卷 113, 期 7, 页码 1444-1454出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-02-142638
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- Landesforschungsschwerpunkt: Mechanismen der Transformation lympho-hamatopoetischer Zellen
- Deutsche Forschungsgemeinschaft [FE-578/1-1]
- Novartis Research Foundation
- NoE network The Epigenome [LSHGCT-2004-503433]
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 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, 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. ( Blood. 2009; 113: 1444-1454)
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