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Novel TAL1 Targets Beyond Protein-Coding Genes: Identification of TAL1-Regulated Micrornas in T-Cell Acute Lymphoblastic Leukemia

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Novel TAL1 Targets Beyond Protein-Coding Genes: Identification of TAL1-Regulated Micrornas in T-Cell Acute Lymphoblastic Leukemia Letters to the Editor 1603 REFERENCES 8 Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent 1 Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med 1995; 333: pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69. 1052–1057. 9 Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D et al. 2 Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S. From pathogenesis to Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010; 10: 37–50. 2011; 365: 1384–1395. 3 Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N et al. Whole- 10 Damm F, Nguyen-Khac F, Fontenay M, Bernard OA. Spliceosome and other novel genome sequencing identifies recurrent mutations in chronic lymphocytic leu- mutations in chronic lymphocytic leukemia and myeloid malignancies. Leukemia kaemia. Nature 2011; 475: 101–105. 2012; 26: 2027–2031. 4 Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L et al. Exome 11 Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in RNP machine. Cell 2009; 136: 701–718. chronic lymphocytic leukemia. Nat Genet 2012; 44: 47–52. 12 David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways 5 Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and programs unhinged. Genes Dev 2010; 24: 2343–2364. and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 13 Corrionero A, Minana B, Valcarcel J. Reduced fidelity of branch point recognition 2011; 365: 2497–2506. and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 6 Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, Messina M et al. Mutations of 2011; 25: 445–459. the SF3B1 splicing factor in chronic lymphocytic leukemia: association with pro- 14 Le Hir H, Andersen GR. Structural insights into the exon junction complex. Curr gression and fludarabine-refractoriness. Blood 2011; 118: 6904–6908. Opin Struct Biol 2008; 18: 112–119. 7 Quesada V, Ramsay AJ, Lopez-Otin C. Chronic lymphocytic leukemia with SF3B1 15 Okada M, Ye K. Nuclear phosphoinositide signaling regulates messenger RNA mutation. N Engl J Med 2012; 366: 2530. export. RNA Biol 2009; 6: 12–16. Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia Leukemia (2013) 27, 1603–1606; doi:10.1038/leu.2013.63 being downregulated (Figures 1b–f). The three remaining micro- RNAs were excluded from subsequent analyses, as we stringently considered only those genes to be validated whose expression The basic helix-loop-helix transcription factor TAL1 is aberrantly was regulated in the predicted manner upon both TAL1 expressed in a majority of T-cell acute lymphoblastic leukemia overexpression and silencing (data not shown). (T-ALL) cases characterized by arrested development in the thymic Next, we evaluated whether the validated microRNAs were late cortical stage.1,2 Although TAL1 is a bona fide T-cell direct targets of TAL1 in T-ALL cells. For this purpose, we oncogene,3 with known direct targets in T-ALL,4 the aberrant scrutinized publicly available TAL1 ChIP-seq data (GEO accession transcriptional circuitry responsible for thymocyte transformation number GSE29181) for two T-ALL cell lines (JURKAT and is not yet fully understood. MicroRNAs are small, non-coding RNAs CCRF-CEM) and two primary T-ALL samples4 for the presence of that function as endogenous post-transcriptional repressors of TAL1-binding peaks up to 10 kb upstream of the transcription start protein-coding genes by binding to target sites in the 30-UTR of site of each microRNA gene. We identified one peak in a putative messenger RNAs.5 Aberrant expression of these molecules has promoter region for miR-146b (Supplementary Figure 1a), sug- been reported in several hematological malignancies, and gesting that this gene may be a transcriptional target of TAL1. microRNA expression signatures delineate ALL subgroups6 and Furthermore, two peaks were observed upstream of miR-223 can be interpreted in light of their variation during transcription start site (Supplementary Figure 1b). To confirm hematopoiesis.7 Individual microRNAs and networks have been these findings, we performed TAL1 ChIP-quantitative PCR in implicated in T-ALL,8 but the mechanisms responsible for altered JURKAT and CCRF-CEM cells using primers designed for the microRNA expression in this malignancy remain poorly explored. genomic areas covered by the two peaks in the miR-223 locus. We Here, we report the identification of novel, non-protein-coding confirmed that there is more than twofold enrichment, as TAL1 target genes, implicating microRNA genes as part of the compared with a mock ChIP performed against fibrillarin, in the transcriptional network downstream of TAL1 that may be amplified area within 3.5 kb upstream of the miR-223 transcription putatively involved in its oncogenic properties. start site (Figure 1g). These results indicate that miR-223 is a direct To identify a TAL1-dependent microRNA gene expression target of TAL1 in T-ALL. Interestingly, TAL1 appears to bind to a profile, we ectopically expressed TAL1 in the TAL1-negative previously described region containing a conserved proximal T-ALL cell line P12 and performed low-density array analysis (see genomic element with possible binding sites for the transcription Supplementary Data online for materials and methods). From 204 factor C/EBP.9 We did not find evidence from the available TAL1 detected microRNAs (out of 372 analyzed), we identified eight ChIP-seq data for direct binding of TAL1 to the remaining microRNA whose expression changed significantly upon TAL1 overexpres- genes, suggesting that miR-135a, miR-330-3p and miR-545 are sion (Figure 1a and Supplementary Tables 1 and 2). Subsequent indirectly regulated by TAL1, at least in the T-ALL cells analyzed. validation was performed by quantitative PCR analysis of each Interestingly, analysis of microRNA gene expression profiles in microRNA after enforcing or silencing the expression of TAL1. This different T-ALL subsets8 revealed that TAL/LMO primary samples allowed us to confirm the expected TAL1-mediated regulation for (integrating Sil-Tal1 þ and LMO þ cases, which frequently express five microRNAs: namely, miR-135a, miR-223 and miR-330-3p as high TAL1 levels) display higher levels of miR-223 (P ¼ 0.035) and being upregulated by TAL1; and miR-146b-5p and miR-545 as tend to express lower levels of miR-146b-5p (P ¼ 0.092) than other Accepted article preview online 1 March 2013; advance online publication, 26 March 2013 & 2013 Macmillan Publishers Limited Leukemia (2013) 1567 – 1614 Letters to the Editor 1604 Figure 1. Identification of TAL1-regulated microRNA genes. (a) Heat map of differentially expressed microRNAs upon TAL1 overexpression. MicroRNAs were hierarchically clustered (rows, microRNAs; columns, experiments). See Supplementary Table 2 for fold-difference values. Levels greater than or less than the mean are shown in shades of red or blue, respectively. (b–f) Quantitative PCR (qPCR) validation of microRNA expression modulation by TAL1. Relative expression of hsa-miR-135a (b), hsa-miR-223 (c), hsa-miR-330-3p (d), hsa-miR-146b-5p (e), and hsa-miR-545 (f) normalized to SNORD38B in T-ALL cell lines with overexpression (left) or knockdown of TAL1 (right). The bars represent the mean±s.d. of three independent replicates. siNT—non-targeting siRNA (g) TAL1 ChIP-qPCR in T-ALL cell lines. The occupancy by TAL1 of the genomic regions 9.2 and 3.5 kb upstream of miR-223 transcription start site was analyzed by ChIP-qPCR in JURKAT and CCRF-CEM cells. The promoter region of LCP2 was used as positive control for TAL1 binding, and a random intergenic region was used as negative control. TAL1 binding is expressed as the fold enrichment relative to a mock ChIP performed against fibrillarin. The error bars represent the 95% CI of the fold enrichment. The horizontal line denotes the fold enrichment detection for the negative control. T-ALL cases (Supplementary Figure 2). In line with these (Supplementary Figure 3b), in agreement with the notion that observations, miR-223 appears to follow the same pattern of TAL1 positively regulates both genes. In contrast, miR-146b-5p is expression along normal human thymocyte development as clearly upregulated in the double-positive to single-positive TAL1,10 with high levels in CD34 þ T-cell precursors and sharp transition and is amongst the most upregulated microRNAs in downregulation in more differentiated subsets (Supplementary mature, single-positive thymocytes.11 The fact that miR-146b-5p Figure 3a). A similar pattern was observed for miR-135a levels associate with thymocyte maturation (Supplementary Leukemia (2013) 1567 – 1614 & 2013 Macmillan Publishers Limited Letters to the Editor 1605 Figure 2. Potential participation of the newly identified TAL1 microRNA target genes in TAL1-mediated leukemogenic pathways. Cross- examination of congruent TAL1-regulated protein-coding and miRNA genes was performed as described in Supplementary Methods. (a) Downregulated miRNAs and their predicted target genes previously shown to be upregulated by TAL1. (b) Upregulated miRNAs and their predicted target genes previously shown to be downregulated by TAL1. Genes are color-coded according to their reported function in the context of cancer, as detailed in Supplementary Tables 3 and 4. ‘Tumor suppressor-like’: bona fide or putative tumor suppressors or genes that have proapoptotic, antiproliferative or prodifferentiating roles; ‘Oncogene-like’: bona fide or putative oncogenes or genes that have antiapoptotic or proliferative roles.
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