microRNAs regulate TAL1 expression in T-cell acute lymphoblastic leukemia

The transcription factor TAL1 is a proto-oncogene whose aberrant expression in committed T-cell precursors is associated with the development of T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms leading to aberrant activation of TAL1 in T-ALL patients who lack chromosomal rearrangements involving the TAL1 locus remain largely unknown. We hypothesized that TAL1 levels decrease during normal T-cell development at least in part due to miRNA-dependent silencing, in which case TAL1 over-expression in some T-ALL cases could be the consequence of deregulated miRNA expression. By performing computational prediction of miRNAs that bind to the human TAL1 mRNA we compiled a list of miRNAs that are candidates to regulate TAL1. Using a luciferase reporter system and mutagenesis assays we confirmed the miRNA-TAL1 mRNA interactions and selected candidate miRNAs: miR-101, miR-520d-5p, miR-140-5p, miR-448 and miR-485-5p. Over-expression of these microRNAs in different T-ALL cell lines consistently resulted in the down-regulation of TAL1 protein. In accordance, inhibition of miR-101 and miR-520d-5p promoted TAL1 protein expression. Importantly, we found that miR-101, miR-140-5p, miR-448 and miR-485-5p were down-regulated in T-ALL patient specimens and T-ALL cell lines. Our results show for the first time the existence of epigenetic regulation of TAL1 by specific miRNAs which may contribute, at least in part, to the ectopic expression of TAL1 in some T-ALL cases.These studies were financed by Liga Portuguesa Contra o Cancro (Terry Fox Award) and by Fundacao para a Ciencia e a Tecnologia (project PTDC/BIM-ONC/1548/2012). NCC received an FCT-SFRH PhD fellowship. JTB is supported by an FCT Consolidation Grant. The Cell Division and Cancer group of the CNIO is funded by the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2012-38215: Consolider-Ingenio 2010 Programme SAF2014-57791-REDC; Red Tematica CellSYS BFU2014-52125-REDT), and the Comunidad de Madrid (OncoCycle Programme S2010/BMD-2470).S