MicroRNAs regulate TAL1 expression in T-cell acute lymphoblastic leukemia.

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

doi:10.18632/oncotarget.6987

Abstract

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.

Highlights

In physiologic conditions, the basic helix-loop-helix transcription factor TAL1 is necessary for hematopoietic commitment [1,2,3], being expressed very early on in hematopoietic differentiation and silenced during normal T-cell lymphopoiesis from the early thymic progenitor stage onwards [4]
While it is known that TAL1 regulates the expression of numerous miRNA genes [27, 28], several observations led us to hypothesize that upstream miRNA networks could be involved in potentiating TAL1 overexpression in T-cell acute lymphoblastic leukemia (T-ALL)
TAL1 is a putative target of several miRNAs that are up-regulated in hematopoietic stem cells, such as hsa-miR-17-5p, hsa-miR-197, hsamiR-106 and hsa-miR-20 [39], and of some that are down-regulated in differentiated megakaryocytes, such as hsa-miR-106 and hsa-miR-20 [40], suggesting that miRNAs might regulate TAL1 at different stages of hematopoietic development

Summary

Introduction

The basic helix-loop-helix transcription factor TAL1 is necessary for hematopoietic commitment [1,2,3], being expressed very early on in hematopoietic differentiation and silenced during normal T-cell lymphopoiesis from the early thymic progenitor stage onwards [4]. The most frequent chromosomal alteration involving the TAL1 locus is the micro-deletion that fuses the TAL1 coding region to the SIL regulatory elements, producing the SIL-TAL1 fusion gene This alteration occurs in 9–25% of childhood T-ALLs driving the aberrant monoallelic expression of TAL1 [8]. The exact frequency of TAL1-positive T-ALL cases due to these newly identified events remains to be determined, and a fraction of cases with TAL1 monoallelic aberrant expression, as well as those with ectopic biallelic activation, remain to be explained. In this context, regulation by non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) [13] has not yet been thoroughly explored as a possible mechanism of epigenetic regulation of TAL1 expression in physiologic conditions or in malignancy

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Results

Conclusion