MLL5 contributes to hematopoietic stem cell fitness and homeostasis.
MLL5 is a novel trithorax group gene and a candidate tumor suppressor gene located within a 2.5-Mb interval of chromosome band 7q22 that frequently is deleted in human myeloid malignancy. Here we show that inactivation of the Mll5 gene in mice results in a 30% reduction in the average representation of hematopoietic stem cells and in functional impairment of long-term hematopoietic repopulation potential under competitive conditions. Bone marrow cells from Mll5-deficient mice were defective in spleen colony-forming assays, and the mutant mice showed enhanced susceptibility to 5-fluorouracil-induced myelosuppression. Heterozygous and homozygous Mll5 mutant mice did not spontaneously develop hematologic cancers, and loss of Mll5 did not alter the phenotype of a fatal myeloproliferative disorder induced by oncogenic Kras in vivo. Collectively, the data reveal an important role for Mll5 in HSC homeostasis and provide a basis for further studies to explore its role in leukemogenesis.
Zhang
Yan
Y
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414, USA.
Wong
Jasmine
J
Klinger
Mark
M
Tran
Mary T
MT
Shannon
Kevin M
KM
Killeen
Nigel
N
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology; D005472:Fluorouracil / Q000633:toxicity; D015870:Gene Expression / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D019426:Integrases / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013154:Spleen / Q000166:cytology
D000964:Antimetabolites, Antineoplastic; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C539231:MLL5 protein, mouse; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D005472:Fluorouracil