title: The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice.
abstract: The miR-17-92 cluster and its 6 encoded miRNAs are frequently amplified and aberrantly expressed in various malignancies. This study demonstrates that retroviral-mediated miR-17-92 overexpression promotes expansion of multipotent hematopoietic progenitors in mice. Cell lines derived from these miR-17-92-overexpressing mice are capable of myeloid and lymphoid lineage differentiation, and recapitulate the normal lymphoid phenotype when transplanted to nonobese diabetic/severe combined immunodeficiency mice. However, overexpression of individual miRNAs from this locus, miR-19a or miR-92a, results in B-cell hyperplasia and erythroleukemia, respectively. Coexpression of another member of this cluster miR-17, with miR-92a, abrogates miR-92a-induced erythroleukemogenesis. Accordingly, we identified several novel miR-92a and miR-17 target genes regulating erythroid survival and proliferation, including p53. Expression of this critical target results in marked growth inhibition of miR-92a erythroleukemic cells. In both murine and human leukemias, p53 inactivation contributed to the selective overexpression of oncogenic miR-92a and miR-19a, and down-regulation of tumor-suppressive miR-17. This miR-17-92 expression signature was also detected in p53- B-cell chronic lymphocytic leukemia patients displaying an aggressive clinical phenotype. These results revealed that imbalanced miR-17-92 expression, also mediated by p53, directly transforms the hematopoietic compartment. Thus examination of such miRNA expression signatures should aid in the diagnosis and treatment of cancers displaying miR-17-92 gene amplification.
authors.affiliation: Department of Medical Biophysics, University of Toronto, and Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Li
authors.forename: Laura M
authors.initials: LM
authors.lastname: Vecchiarelli-Federico
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Li
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: David
authors.initials: D
authors.lastname: Spaner
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Hough
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000502:physiology; D041681:NIH 3T3 Cells; D062085:RNA, Long Noncoding
chemical_list: C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding