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Downregulation of Microrna-142 by Proto-Oncogene LMO2 and Its Co-Factors

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Downregulation of Microrna-142 by Proto-Oncogene LMO2 and Its Co-Factors Letters to the Editor 1067 previously described BCL6/IG translocations with a breakpoint P Bertrand1, C Maingonnat1, JM Picquenot1, N Dastugue2, 1 2 1 1 in the 50 UTR of BCL6, or in the distant ABR.2,6 Thus, in our D Penther , L Ysebaert , C Maisonneuve , H Tilly and C Bastard1 cases BCL6 deregulation can not be explained by promoter 1 substitution. In case no. 2 the inactivation of BCL6 negative Groupe d’e´tude des prolife´rations lymphoı¨des, INSERM U918, IFRMP23, Centre Henri Becquerel, Rouen, France and autoregulation sites by mutations can be hypothesized, but in 2INSERM U563, Centre de Physiopathologie, case no.1, for which no mutation was found inside these Toulouse, France regions, the most reliable hypothesis involves cis-acting E-mail: [email protected] elements provided by the partner sequences. The expression of TMEM75, the closest locus brought by the translocation was References investigated. The transcript was detected, at a level which did not differ significantly from the mean level of the 11 previous 1 Bertrand P, Bastard C, Maingonnat C, Jardin F, Maisonneuve C, controls. Thus, the activation of BCL6 by TMEM75 regulating Courel MN et al. Mapping of MYC breakpoints in 8q24 rearrange- sequences remains possible, but the effects of more distant ments involving non-immunoglobulin partners in B-cell lympho- regions can not be precluded. Indeed, it was demonstrated that mas. Leukemia 2007; 21: 515–523. enhancers, defined as position and orientation independent 2 Butler MP, Iida S, Capello D, Rossi D, Rao PH, Nallasivam P et al. 0 activators of transcription, can exert regulating effects several Alternative translocation breakpoint cluster region 5 to BCL-6 in B-cell non-Hodgkin’s lymphoma. Cancer Res 2002; 62: hundred kilobases from targets by DNA folding, thus bringing 7 4089–4094. together enhancer and the target. 3 Lossos IS, Levy R. Mutation analysis of the 50 noncoding regulatory Regarding the pathophysiological role of the t(3;8), several region of the BCL-6 gene in non-Hodgkin lymphoma: evidence for hypotheses can be raised as: (i) BCL6 expression was recurrent mutations and intraclonal heterogeneity. Blood 2000; 95: significantly increased as compared to controls although the 1400–1405. effects of mutations located in negatively regulating region 4 Jardin F, Buchonnet G, Parmentier F, Contentin N, Lepretre S, Lenain P et al. Follicle center lymphoma is associated with could also explain the gene overexpression; (ii) we have shown significantly elevated levels of BCL-6 expression among lymphoma previously that, in these cases MYC transcript was also subtypes, independent of chromosome 3q27 rearrangements. overexpressed; (iii) the formation of MYC-BCL6 complexes at Leukemia 2002; 16: 2318–2325. the protein level has been reported,8 with an effect on MYC half- 5 Kikuchi M, Miki T, Kumagai T, Fukuda T, Kamiyama R, Miyasaka N life, suppression of the synthesis of the p21CIP cell cycle arrest et al. Identification of negative regulatory regions within the gene, and inhibition of BCL6 acetylation. Therefore, the first exon and intron of the BCL6 gene. Oncogene 2000; 19: 4941–4945. synergistic effect of MYC and BCL6 could explain the survival 6 Akasaka H, Akasaka T, Kurata M, Ueda C, Shimizu A, Uchiyama T and clonal selection of a t(3;8) carrying cell in lymphoma et al. Molecular anatomy of BCL6 translocations revealed by long- progression. distance polymerase chain reaction-based assays. Cancer Res 2000; 60: 2335–2341. 7 Ratsch A, Joos S, Kioschis P, Lichter P. Topological organization of Acknowledgements the MYC/IGK locus in Burkitt’s lymphoma cells assessed by nuclear halo preparations. Exp Cell Res 2002; 273: 12–20. 8 Saito M, Phan RT, Morse HC, Pasqualucci L, Dalla-Favera R. This work was supported by the Ligue Contre le Cancer (Comite´ Pathologic co-expression and physical interaction of c-MYC and de Seine Maritime) and the Fe´de´ration des Centres de Lutte contre BCL6 in B-cell lymphomas. Blood (Am Soc Hematol Annu Meet le Cancer. Abstr) 2005; 106, (abstract [2]). Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu) Downregulation of microRNA-142 by proto-oncogene LMO2 and its co-factors Leukemia (2008) 22, 1067–1071; doi:10.1038/sj.leu.2405001; LMO2 functions as a bridging molecule with the two arms of published online 1 November 2007 GATA1 and TAL1/E47 bound to relevant DNA motifs.4 MicroRNAs (miRNAs) are a recently discovered class of small Hematopoiesis is a tightly regulated multistage process. In the (E22-nt), non-coding RNAs that regulate gene expression via past decade, a number of transcription factors have been the RNA interference pathway either to promote degradation of identified as crucial regulators in cell proliferation, differentia- the target mRNA or to repress its translation. There was tion and apoptosis in hematopoiesis. The proto-oncogene, increasing evidence showing that miRNAs had crucial functions LMO2 (also named rbtn2 or ttg2), is such a factor. LMO2 was in hematopoiesis, as well as leukemia (reviewed in Ref. 5). first cloned from an acute T-lymphocyte leukemia (T-ALL) However, there were only a few reports about the expression patient with a (11;14;p13;q11) translocation,1 and subsequently profiles of miRNAs, and studies on miRNA expression regula- showed crucial functions in hematopoiesis, as well as in tions in hematopoiesis are limited. Until now, the best studied is angiogenesis.2,3 LMO2 encodes a LIM-only protein comprised miR-223, which has been shown to be regulated by C/EBPa6, of two LIM domains characterized as a cysteine-rich motif PU.1 and GATA1.7 consisting of two tandemly repeated zinc fingers and is MiR-142, which was confirmed to have similar functions with considered to be a transcriptional regulator through the miR-223 in promoting T-cell development, has rarely been interactions with its partners, including LDB1 (CLIM2/NLI1), studied before. In this study, we analyzed miR-142 expression GATA1, TAL1(SCL) and E47, to form a multi-complex in which profiles in the human erythroid/myeloid leukemia cell line, Leukemia Letters to the Editor 1068 Figure 1 MiR-142 expression was correlated with LMO2. (a) Expression levels of miR-142 and LMO2 were shown by reverse transcriptase (RT)–PCR analysis. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal control. The agarose gel electrophoresis data was quantified by UV Band scanning. Data represent three independent experiments. (b) LMO2 protein expression was detected by western blot analysis using monoclonal anti-LMO2 antibody. K562, the human T-cell lymphoblast-like cell line, Jurkat, and specific genes found to be directly regulated by the LMO2 the Burkitt lymphoma cell line, Raji, by semi-quantitative RT– complex.8 In addition, there were also two predicted transcrip- PCR. MiR-142 was detected in all these cell lines. We then tional start sites in this region, as shown in Figure 2a (committed analyzed LMO2 mRNA levels by semi-quantitative RT–PCR and by NNPP Neural Network Promoter Prediction; http:// LMO2 protein expression by immunoblot analysis in these cell www.fruitfly.org/seq_tools/promoter.html), but they seemed to lines. We found that LMO2 expression (both mRNA and protein) contribute with no prominent difference to the promoter activity was absent in Jurkat cells, which expressed high levels of miR- (Figure 2b N2 and N3). 142. In contrast, the other two cell lines that expressed high To investigate whether LMO2 physically interacted with the levels of LMO2 showed reduced miR-142 expression (Figure 1). miR-142 promoter region in vivo, we performed ChIP in K562 These data suggested that there might be some relationship cells. Anti-LMO2 antibody, as well as anti-FLAG antibody used between miR-142 and LMO2. as a control, was used to immunoprecipitate the fragmented To identify possible regulators of miR-142 expression, we chromatin. After reversal of the crosslink, a segment of the miR- cloned a 2320 bp region 50 flanking of pre-miR-142 from the 142 promoter (À2000 to À1703 bp, 298 bp) containing the human genome and then confirmed by sequencing, named N1 E-box/GATA site was amplified by PCR using specific spanning (À2320 to À1 bp). Then a set of 50 deletions were performed primers. Primers recognizing the 30-distal region were used as a according to the restriction sites that were suitable for insertions negative control in the PCR reactions, as shown in Figure 3a. to pGL4 vector and another two reporter constructs, named N2 The result suggested that LMO2 could specifically bind to the (À1274 to À1 bp) and N3 (À1144 to À1 bp), were generated. À2000 to À1703 bp (298 bp) region of the miR-142 promoter These constructs were assayed in transient transfection experi- (Figure 3b), providing strong evidence that LMO2 was involved ments in K562 and control (HEK293) cell lines. All these in the regulation of the miR-142 gene. reporters showed potent promoter activity in K562 cells, in To further study, the regulatory effect of LMO2 on the which the miR-142 gene was endogenously expressed. How- miR142-promoter, we performed a LMO2 overexpression assay ever, the reporters were virtually silent in the control cell line. and knockdown assay using RNAi. The LMO2 siRNA construct One notable thing was that the promoter activity was (pSilencer4.1-siLMO2), or an unrelated control siRNA construct significantly increased when the À2320 to À1274 region was (pSilencer4.1-control), was transfected into K562 cells. LMO2 deleted. This indicated that this region might contain some silencing efficiency was confirmed using western blot analysis repressor elements contributing to the regulating miR-142 and the results showed that the protein level was reduced to less expression in K562 cells (Figure 2b).
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