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Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia

Leukemia volume 27, pages 1603–1606 (2013)Cite this article

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The basic helix-loop-helix transcription factor TAL1 is aberrantly expressed in a majority of T-cell acute lymphoblastic leukemia (T-ALL) cases characterized by arrested development in the thymic late cortical stage.1, 2 Although TAL1 is a bona fide T-cell oncogene,3 with known direct targets in T-ALL,4 the aberrant transcriptional circuitry responsible for thymocyte transformation is not yet fully understood. MicroRNAs are small, non-coding RNAs that function as endogenous post-transcriptional repressors of protein-coding genes by binding to target sites in the 3′-UTR of messenger RNAs.5 Aberrant expression of these molecules has been reported in several hematological malignancies, and microRNA expression signatures delineate ALL subgroups6 and can be interpreted in light of their variation during hematopoiesis.7 Individual microRNAs and networks have been implicated in T-ALL,8 but the mechanisms responsible for altered microRNA expression in this malignancy remain poorly explored. Here, we report the identification of novel, non-protein-coding TAL1 target genes, implicating microRNA genes as part of the transcriptional network downstream of TAL1 that may be putatively involved in its oncogenic properties.

Next, we evaluated whether the validated microRNAs were direct targets of TAL1 in T-ALL cells. For this purpose, we scrutinized publicly available TAL1 ChIP-seq data (GEO accession number GSE29181) for two T-ALL cell lines (JURKAT and CCRF-CEM) and two primary T-ALL samples4 for the presence of TAL1-binding peaks up to 10 kb upstream of the transcription start site of each microRNA gene. We identified one peak in a putative promoter region for miR-146b (Supplementary Figure 1a), suggesting that this gene may be a transcriptional target of TAL1. Furthermore, two peaks were observed upstream of miR-223 transcription start site (Supplementary Figure 1b). To confirm these findings, we performed TAL1 ChIP-quantitative PCR in JURKAT and CCRF-CEM cells using primers designed for the genomic areas covered by the two peaks in the miR-223 locus. We confirmed that there is more than twofold enrichment, as compared with a mock ChIP performed against fibrillarin, in the amplified area within 3.5 kb upstream of the miR-223 transcription start site (Figure 1g). These results indicate that miR-223 is a direct target of TAL1 in T-ALL. Interestingly, TAL1 appears to bind to a previously described region containing a conserved proximal genomic element with possible binding sites for the transcription factor C/EBP.9 We did not find evidence from the available TAL1 ChIP-seq data for direct binding of TAL1 to the remaining microRNA genes, suggesting that miR-135a, miR-330-3p and miR-545 are indirectly regulated by TAL1, at least in the T-ALL cells analyzed.

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Acknowledgements

This study was supported by grants from Fundação para a Ciência e a Tecnologia (FCT; PTDC/BIM-ONC/1548/2012) and Liga Portuguesa Contra o Cancro (Terry Fox Award) to JTB; and FWO Vlaanderen (G056413N) and UGent (GOA 01G01910W) to FS. NCC and KD have PhD fellowships from FCT and IWT Vlaanderen, respectively. PR has a post-doctoral grant from FWO Vlaanderen. We would like to thank Steve Lefever for primer design.

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  1. Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    N C Correia, A P Leite, F J Enguita & J T Barata

  2. Department of Pediatrics and Genetics, Center for Medical Genetics, Ghent University, Ghent, Belgium

    K Durinck, M Ongenaert, P Rondou & F Speleman

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  1. N C Correia
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Correspondence to J T Barata.

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Correia, N., Durinck, K., Leite, A. et al. Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia. Leukemia 27, 1603–1606 (2013). https://doi.org/10.1038/leu.2013.63

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