title: miR-433 is aberrantly expressed in myeloproliferative neoplasms and suppresses hematopoietic cell growth and differentiation.
abstract: BCR-ABL-negative myeloproliferative neoplasms (MPNs) are most frequently characterized by the JAK2V617F gain-of-function mutation, but several studies showed that JAK2V617F may not be the initiating event in MPN development, and recent publications indicate that additional alterations such as chromatin modification and microRNA (miRNA) deregulation may have an important role in MPN pathogenesis. Here we report that 61 miRNAs were significantly deregulated in CD34+ cells from MPN patients compared with controls (P<0.01). Global miRNA analysis also revealed that polycythemia vera (JAKV617F) and essential thrombocythemia (JAK2 wild type) patients have significantly different miRNA expression profiles from each other. Among the deregulated miRNAs, expression of miR-134, -214 and -433 was not affected by changes in JAK2 activity, suggesting that additional signaling pathways are responsible for the deregulation of these miRNAs in MPN. Despite its upregulation in MPN CD34+ and during normal erythropoiesis, both overexpression and knockdown studies suggest that miR-433 negatively regulates CD34+ proliferation and differentiation ex vivo. Its novel target GBP2 is downregulated during normal erythropoiesis and regulates proliferation and erythroid differentiation in TF-1 cells, indicating that miR-433 negatively regulates hematopoietic cell proliferation and erythropoiesis by directly targeting GBP2.
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: K L
authors.initials: KL
authors.lastname: Rice
authors.forename: M
authors.initials: M
authors.lastname: Buzzai
authors.forename: E
authors.initials: E
authors.lastname: Hexner
authors.forename: F F
authors.initials: FF
authors.lastname: Costa
authors.forename: O
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: A
authors.initials: A
authors.lastname: Mullally
authors.forename: M B
authors.initials: MB
authors.lastname: Soares
authors.forename: B L
authors.initials: BL
authors.lastname: Ebert
authors.forename: R
authors.initials: R
authors.lastname: Levine
authors.forename: J D
authors.initials: JD
authors.lastname: Licht
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; C548883:MIRN433 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D008156:Luciferases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C534329:GBP2 protein, human; D019204:GTP-Binding Proteins