title: Complex oncogene dependence in microRNA-125a-induced myeloproliferative neoplasms.
abstract: Deregulation of microRNA (miRNA) expression can lead to cancer initiation and progression. However, limited information exists on the function of miRNAs in cancer maintenance. We examined these issues in the case of myeloproliferative diseases and neoplasms (MPN), a collection of hematopoietic neoplasms regarded as preleukemic, thereby representing early neoplastic states. We report here that microRNA-125a (miR-125a)-induced MPN display a complex manner of oncogene dependence. Following a gain-of-function genomics screen, we overexpressed candidate miR-125a in vivo, which led to phenotypes consistent with an atypical MPN characterized by leukocytosis, monocytosis, splenomegaly, and progressive anemia. The diseased MPN state could be recapitulated in a doxycycline-inducible mouse model. Upon doxycycline withdrawal, the primary MPN phenotypes rapidly resolved after the discontinuation of miR-125a overexpression. However, reinduction of miR-125a led to complex phenotypes, with some animals rapidly developing lethal anemia with extensive damages in the spleen. Forced expression of miR-125a resulted in elevated cellular tyrosine phosphorylation and hypersensitivity toward hematopoietic cytokines. Furthermore, we demonstrate that miR-125a targets multiple protein phosphatases. Our data demonstrate that miR-125a-induced MPN is addicted to its sustained overexpression, and highlight the complex nature of oncogenic miRNA dependence in an early neoplastic state.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Shangqin
authors.initials: S
authors.lastname: Guo
authors.forename: Haitao
authors.initials: H
authors.lastname: Bai
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Megyola
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halene
authors.forename: Diane S
authors.initials: DS
authors.lastname: Krause
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019046:Bone Marrow Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004318:Doxycycline / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007377:Interleukin-3; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004318:Doxycycline