Downregulation of microRNA-142 by proto-oncogene LMO2 and its co-factors

Abstract

previously described BCL6/IG translocations with a breakpoint in the 5 0 UTR of BCL6, or in the distant ABR. 2,6 Thus, in our cases BCL6 deregulation can not be explained by promoter substitution. In case no. 2 the inactivation of BCL6 negative autoregulation sites by mutations can be hypothesized, but in case no.1, for which no mutation was found inside these regions, the most reliable hypothesis involves cis-acting elements provided by the partner sequences. The expression of TMEM75, the closest locus brought by the translocation was investigated. The transcript was detected, at a level which did not differ significantly from the mean level of the 11 previous controls. Thus, the activation of BCL6 by TMEM75 regulating sequences remains possible, but the effects of more distant regions can not be precluded. Indeed, it was demonstrated that enhancers, defined as position and orientation independent activators of transcription, can exert regulating effects several hundred kilobases from targets by DNA folding, thus bringing together enhancer and the target. 7 Regarding the pathophysiological role of the t(3;8), several hypotheses can be raised as: (i) BCL6 expression was significantly increased as compared to controls although the effects of mutations located in negatively regulating region could also explain the gene overexpression; (ii) we have shown previously that, in these cases MYC transcript was also overexpressed; (iii) the formation of MYC-BCL6 complexes at the protein level has been reported, 8 with an effect on MYC halflife, suppression of the synthesis of the p21 CIP cell cycle arrest gene, and inhibition of BCL6 acetylation. Therefore, the synergistic effect of MYC and BCL6 could explain the survival and clonal selection of a t(3;8) carrying cell in lymphoma progression.

Regulation of LMO2 mRNA and protein expression in erythroid differentiation

“…15 Of considerable interest given its own regulation by an miRNA, LMO2 was recently implicated in down-regulating miRNA-142. 16 In summary, recent studies, including the one reported by Felli et al 10 , have shown that LMO2 is regulated at both a posttranscriptional and post-translational level in erythroid progenitors. This undoubtedly contributes to the precision with which erythrocyte production is controlled in vivo.…”

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

“…To date, very few miRNAs have been shown to play important roles in HSC development in vertebrates in vivo. miR-142-3p is specifically expressed in HSCs (AGM and CHT) and T cells (thymus) in zebrafish, mouse and other species [15][16][17][18][19][20][21]. By knockdown of miR-142a-3p using 2 specific MOs, the numbers of HSCs and T cells were decreased.…”

“…In addition, miR-144 and miR-451, as direct targets of the critical hematopoietic master regulator GATA1, are required for erythropoiesis in zebrafish and mouse [11][12][13]. miR-142-3p is an evolutionally conserved miRNA of vertebrates, which is expressed in many different hematopoietic cells [14][15][16][17][18][19][20][21]. Chen et al [15] first reported that miR-142 is expressed in embryonic and adult hematopoietic tissues, including the fetal liver, bone marrow, spleen and thymus, in mice, indicating its role in both embryonic and adult hematopoiesis.…”

miR-223 and miR-142 attenuate hematopoietic cell proliferation, and miR-223 positively regulates miR-142 through LMO2 isoforms and CEBP-β

“…These results indicate that the primary transcript of miR-142 is about 750 bp in length, and that there are no introns in this gene. In our previous study, it was demonstrated that LMO2 could negatively regulate the expression of miR-142 by binding to a typical LMO2 binding site located in the upstream region of the miR-142 locus [39]. In addition, the TESS online transcription element search system (http:// www.cbil.upenn.edu) revealed that there are two typical CEBP-β sites in the 2 kb promoter region, as indicated in Figure 2D.…”