期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 155, 期 1, 页码 73-83出版社
WILEY
DOI: 10.1111/j.1365-2141.2011.08812.x
关键词
acute lymphoblastic leukaemia; epigenetics; microRNAs; MIR9; oncogenic pathways
类别
资金
- Ministerio de Ciencia e Innovacion and Instituto de Salud Carlos III (ISCIII) [PI07/0602, PI10/00110, PI10/01691, RTICC RD06/0020]
- Contrato Miguel Servet [CP07/00215]
- European FEDER funds Interreg IVA (CITTIL)
- Programa Tu Eliges
- Tu Decides (CAN)
- Gobierno de Navarra
- Departamento de Salud
- Beca Ortiz de Landazuri [6/2009]
- Programa Rio Hortega (ISCIII)
- Junta de Andalucia [0004/2007, 0206/2009]
- 'UTE project CIMA'
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.
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