microRNAs regulate TAL1 expression in T-cell acute lymphoblastic leukemia

envie a um amigo share this

microRNAs regulate TAL1 expression in T-cell acute lymphoblastic leukemia

Quarta, 15.06.2016

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy in which the transformed clone is arrested during T-cell development. Despite significant improvements in treatment outcome, survivors tend to face long term complications and develop serious secondary health problems. Therefore, the current challenge is to develop more efficient therapeutic strategies that target the leukemia cells in a more specific way, diminishing the toxic effects of the treatment. To achieve this, it is essential to improve our knowledge regarding the causes, pathophysiology and regulation of T-ALL, in particular by identifying the molecules and pathways fundamental for leukemia progression. TAL1 is an important transcription factor for the maintenance of hematopoietic stem cells and regulation of early hematopoiesis. Aberrant expression of TAL1 in committed T-cell precursors is associated with leukemia and TAL1 is a well-established T-ALL oncogene, being over-expressed in more than 60% of T-ALL patients. However, the mechanisms leading to aberrant activation of TAL1 in the majority of T-ALL patients who lack chromosomal rearrangements remain largely unknown. Our results, recently published in Oncotarget, provide evidence that TAL1 levels decrease during normal T-cell development at least in part due to microRNA-dependent down-regulation, in which case TAL1 over-expression in some T-ALL cases is likely the consequence, at least in part, of diminished microRNA expression. More broadly, our findings reveal that TAL1 is post-transcriptionally regulated by microRNAs.

Nádia C. Correia, Alice Melão, Vanda Póvoa, Leonor Sarmento, Marta Gómez de Cedrón, Marcos Malumbres, Francisco J. Enguita, João T. Barata

Instituto de Medicina Molecular (iMM-Lisboa), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

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.

Oncotarget

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=6987&path[]=20046