title: Deregulation of FGFR1 and CDK6 oncogenic pathways in acute lymphoblastic leukaemia harbouring epigenetic modifications of the MIR9 family.
abstract: The role of epigenetic mechanisms in the regulation of microRNAs (miRNAs) with a tumour-suppressor function in human neoplasms has recently been established. Several miRNAs have been found to be inappropriately regulated by DNA methylation in patients with acute lymphoblastic leukaemia (ALL). We analysed the methylation status of the three members of the MIR9 family (MIR9-1, MIR9-2 and MIR9-3) in a uniformly treated cohort of 200 newly diagnosed ALLs. MIR9 was methylated in 54% of the patients and was associated with downregulation of MIR9 (P < 0·01). Hypermethylation of MIR9 was an independent prognostic factor for disease-free survival, overall survival and event-free survival in a multivariate analysis (P < 0·01). Epigenetic downregulation of MIR9 induced upregulation of its targets, FGFR1 and CDK6, while treatment of ALL cells with FGFR1 (PD-173074) and CDK6 (PD-0332991) inhibitors induced a decrease in cell proliferation and an increase in apoptosis of ALL cells. Our results indicate that the MIR9 family is involved in the pathogenesis and clinical behaviour of ALL and provide the basis for new therapeutic strategies in the treatment of ALL, targeting the epigenetic regulation of miRNAs and/or the FGFR1 or CDK6-RB pathway directly.
authors.affiliation: Division of Cancer, Foundation for Applied Medical Research, Universidad de Navarra, Avenida Pio XII 36, Pamplona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Rodriguez-Otero
authors.forename: José
authors.initials: J
authors.lastname: Román-Gómez
authors.forename: Amaia
authors.initials: A
authors.lastname: Vilas-Zornoza
authors.forename: Edurne San
authors.initials: ES
authors.lastname: José-Eneriz
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martín-Palanco
authors.forename: José
authors.initials: J
authors.lastname: Rifón
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D018899:CpG Islands / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C115711:PD 173074; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D012334:RNA, Neoplasm; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib