title: Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin.
abstract: Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
authors.affiliation: Departments of Medicine and Molecular Virology and Human Genetics, Comprehensive Cancer Center, and College of Pharmacology, Ohio State University, Columbus, OH 43221, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Michela
authors.initials: M
authors.lastname: Garofalo
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Martelli
authors.forename: Roger
authors.initials: R
authors.lastname: Briesewitz
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fernandez-Cymering
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Liso
authors.forename: Daniela
authors.initials: D
authors.lastname: Diverio
authors.forename: Marco
authors.initials: M
authors.lastname: Mancini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Meloni
authors.forename: Robin
authors.initials: R
authors.lastname: Foa
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003593:Cytoplasm / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C090460:HOXB4 protein, human; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D035683:MicroRNAs; D050505:Mutant Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000090243:Nucleophosmin; C069634:HOXA10 protein, human; D051941:fms-Like Tyrosine Kinase 3