title: Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core-binding factor subunits.
abstract: Core-binding factor leukemia (CBFL) is a subgroup of acute myeloid leukemia (AML) characterized by genetic mutations involving the subunits of the core-binding factor (CBF). The leukemogenesis model for CBFL posits that one, or more, gene mutations inducing increased cell proliferation and/or inhibition of apoptosis cooperate with CBF mutations for leukemia development. One of the most common mutations associated with CBF mutations involves the KIT receptor. A high expression of KIT is a hallmark of a high proportion of CBFL. Previous studies indicate that microRNA (MIR) 222/221 targets the 3' untranslated region of the KIT messenger RNA and our observation that AML1 can bind the MIR-222/221 promoter, we hypothesized that MIR-222/221 represents the link between CBF and KIT. Here, we show that MIR-222/221 expression is upregulated after myeloid differentiation of normal bone marrow AC133(+) stem progenitor cells. CBFL blasts with either t(8;21) or inv(16) CBF rearrangements with high expression levels of KIT (CD117) display a significantly lower level of MIR-222/221 expression than non-CBFL blasts. Consistently, we found that the t(8;21) AML1-MTG8 fusion protein binds the MIR-222/221 promoter and induces transcriptional repression of a MIR-222/221-LUC reporter. Because of the highly conserved sequence homology, we demonstrated concomitant MIR-222/221 down-regulation and KIT up-regulation in the 32D/WT1 mouse cell model carrying the AML1-MTG16 fusion protein. This study provides the first hint that CBFL-associated fusion proteins may lead to up-regulation of the KIT receptor by down-regulating MIR-222/221, thus explaining the concomitant occurrence of CBF genetic rearrangements and overexpression of wild type or mutant KIT in AML.
authors.affiliation: Dipartimento di Biologia e Genetica per le Scienze Mediche, Facoltà di Medicina, Università degli Studi di Milano, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brioschi
authors.forename: John
authors.initials: J
authors.lastname: Fischer
authors.forename: Roberto
authors.initials: R
authors.lastname: Cairoli
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossetti
authors.forename: Laura
authors.initials: L
authors.lastname: Pezzetti
authors.forename: Michele
authors.initials: M
authors.lastname: Nichelatti
authors.forename: Mauro
authors.initials: M
authors.lastname: Turrini
authors.forename: Francesca
authors.initials: F
authors.lastname: Corlazzoli
authors.forename: Barbara
authors.initials: B
authors.lastname: Scarpati
authors.forename: Enrica
authors.initials: E
authors.lastname: Morra
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sacchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Beghini
mesh_terms: D000071916:AC133 Antigen; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D004921:Erythropoietin; D006023:Glycoproteins; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D010455:Peptides; D019009:Proto-Oncogene Proteins c-kit; D000075142:RUNX1 Translocation Partner 1 Protein; C107844:AML1-ETO fusion protein, human; C525709:MIR221, human; C525710:MIR222, human; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse