title: Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene.
abstract: Acute myeloid leukemia (AML) with t(8;16)(p11;p13) (t(8;16) AML) has unique clinico-biological characteristics, but its microRNA pattern is unknown. We analyzed 670 microRNAs in seven patients with t(8;16) AML and 113 with other AML subtypes. Hierarchical cluster analysis showed that all t(8;16) AML patients grouped in an independent cluster. Supervised analysis revealed a distinctive signature of 94-microRNAs, most of which were downregulated, including miR-21 and cluster miR-17-92. The mRNA expression analysis of two known transcription factors of these microRNAs (STAT3 and c-Myc, respectively) showed significant downregulation of STAT3 (P=0.04). A bioinformatic analysis showed that 29 of the downregulated microRNAs might be regulated by methylation; we treated a t(8;16) AML sample with 5-aza-2'-deoxycytidine (5-AZA-dC) and trichostatin A and found that 27 microRNAs were re-expressed after treatment. However, there was no difference in methylation status between t(8;16) and other AML subtypes, either overall or in the microRNA promoter. Cross-correlation of mRNA and microRNA expression identified RET as a potential target of several microRNAs. A Renilla-luciferase assay and flow cytometry after transfection with pre-microRNAs confirmed that RET is regulated by miR-218, miR-128, miR-27b, miR-15a and miR-195. In conclusion, t(8;16) AML harbors a specific microRNA signature that is partially epigenetically regulated and targets RET proto-oncogene.
authors.affiliation: Department of Hematology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Díaz-Beyá
authors.forename: A
authors.initials: A
authors.lastname: Navarro
authors.forename: G
authors.initials: G
authors.lastname: Ferrer
authors.forename: T
authors.initials: T
authors.lastname: Díaz
authors.forename: B
authors.initials: B
authors.lastname: Gel
authors.forename: M
authors.initials: M
authors.lastname: Camós
authors.forename: M
authors.initials: M
authors.lastname: Pratcorona
authors.forename: M
authors.initials: M
authors.lastname: Torrebadell
authors.forename: M
authors.initials: M
authors.lastname: Rozman
authors.forename: D
authors.initials: D
authors.lastname: Colomer
authors.forename: M
authors.initials: M
authors.lastname: Monzo
authors.forename: J
authors.initials: J
authors.lastname: Esteve
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives; D014408:Biomarkers, Tumor / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D016000:Cluster Analysis; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D000077209:Decitabine; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C000715470:MAS1 protein, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D000077209:Decitabine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D001374:Azacitidine