title: MicroRNA profiling reveals aberrant microRNA expression in adult ETP-ALL and functional studies implicate a role for miR-222 in acute leukemia.
abstract: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup in acute T-cell lymphoblastic leukemia (T-ALL). To investigate the immature and myeloid nature of ETP-ALL we examined global microRNA (miRNA) expression in adult ETP-ALL. miRNA profiling of ETP-ALL (n=8), non-ETP T-ALL (n=6), and healthy controls was performed and results were validated in independent cohorts of 66 ETP-ALL and 111 non-ETP T-ALL using real-time RT-PCR. Furthermore, in vitro studies were performed on deregulated miRNAs in acute leukemia. We identified miR-221 and miR-222 as the most upregulated and six miRNAs (miR-151-3p, miR-19a, miR-20b, miR-342-3p, miR-363, and miR-576-3p) as downregulated in ETP-ALL compared to non-ETP T-ALL. In the validation cohorts, miR-221 and miR-222 were significantly upregulated in ETP-ALL, and miR-363 and miR-19a were downregulated in ETP-ALL. ETS1, downregulated in ETP-ALL, was identified as direct target of miR-222. In our in vitro studies miR-222 significantly inhibited proliferation, and caused cell cycle arrest and apoptosis in leukemic cells. In conclusion, our study revealed aberrant miRNA expression in ETP-ALL, with miR-221 and miR-222 as the most overexpressed miRNAs and implied a functional role for miR-222 in leukemic cells. Importantly, miR-222 may impact leukemogenesis by altering expression of the proto-oncogene ETS1 in acute leukemia.
authors.affiliation: Hematology and Oncology, Charité, University Hospital Benjamin Franklin, Berlin, Germany.
authors.forename: Ebru
authors.initials: E
authors.lastname: Coskun
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlee
authors.forename: Frauke
authors.initials: F
authors.lastname: Liebertz
authors.forename: Sandra
authors.initials: S
authors.lastname: Heesch
authors.forename: Nicola
authors.initials: N
authors.lastname: Goekbuget
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006801:Humans; D019169:Jurkat Cells; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D046228:Microarray Analysis; D008875:Middle Aged; D054504:Precursor Cells, T-Lymphoid / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; C000715470:MAS1 protein, human; C525710:MIR222, human