Mir-17-92 Cluster Dysregulation in Lymphoid Malignancies: Its Role in Lymphoma Genesis

MicroRNAs (miRNAs) are short, endogenous singled-stranded noncoding RNAs whose dysregulation has been implicated in important biologic processes, including cancer development. The principal mechanism of action of these master regulators is to control gene expression by suppressing mRNA translation and reducing mRNA stability. In particular, the miR-17-92 cluster is one of the most frequently miRNA expressed in different subtypes of non-Hodgkin lymphomas. Its widespread dysregulation in these pathologies suggests this cluster as a new biomarker that may supplement lymphoma diagnosis and prognosis, and also as an attractive target to design novel strategies for cancer therapy. Alejandro Roisman and Irma Slavutsky* Laboratory of Genetics of Lymphoid Neoplasms, Institute of Experimental Medicine, Argentina Irma Slavutsky, et al., Clinics in Oncology Lymphoma Remedy Publications LLC., | http://clinicsinoncology.com/ 2017 | Volume 2 | Article 1210 2 miR18a over expression, exhibiting a reduced proliferating signature and a significantly better prognosis with longer overall survival. This combined analysis of coding and non coding genes in MCL represent a new approach that may contribute to improve the understanding of this pathology. In addition, experimental studies showed that over expression of miR-17-92 mediates chemoand radioresistance and enhances tumor growth in MCL cells, suggesting this cluster as a potential therapeutic target for patients with this lymphoma [13,14]. Studies on CLL patients found increased miR17 expression in unmutated and ZAP-70 positive cases [15]. Furthermore, a diminished miR-17 activity was seen in patients with TP53 mutation/ deletion [16], results that agree with those observed by Li et al. [17] that found low miR-17 and miR-20a and high miR-19a, miR-19b-1 and miR-92a-1 mRNA levels in cases with TP53 alterations in comparison with healthy donors. In addition, there are evidences of the induction of miR-17-92 expression associated with MYC expression induced by the micro environmental, supporting the impact of these stimuli in miRNAs transcriptional regulation [18] as well as the interaction between MYC and miR-17-92 cluster in CLL patients [15]. MYC is a transcription factor that has a key role in promoting tumorigenesis by activating and repressing target genes involved in many pathways associated to malignant development, being one of the most common abnormalities in cancer [19]. As known, DLBCL is the most common type of NHLs, showing three different molecular subtypes with distinct genetic aberrations and clinical outcome. Among them, the miR-17-92 cluster is significantly upregulated in germinal center B-cell (GCB) subtype compared to activated B-cell [20, 21], whereas miR-17 is overexpressed in DLBCL originated within the central nervous system [22]. GCBDLBCL frequently shows amplifications at 13q31.3 region that could be the cause of miR-17-92 upregulation [7]. This mechanism is also observed in patients with Richter ́s syndrome, in which 13q31.3 amplifications are observed at the time of transformation, associated to the gain of MYC and loss of TP53, supporting the involvement of the miR-17-92 cluster in the acquisition of a more biologically aggressive disease [23]. MYC binds to the promoter of the miR-17-92 cluster and to the E2F1 promoter (a transcription factor that promotes G1-to-S phase progression) activating their transcription, while the miR-17-92 repress the expression of E2F1, indicating the presence of a fine-tuned regulatory mechanism of proliferation [24]. In addition, miR-17-92 cluster also impacts on B-Cell Receptor (BCR) signaling. Microarray studies showed MYC and MIR17HG loci amplifications, consistent with the high level of MYC and members of miR-17-92 cluster required for DLBCLs to sustain BCR response, suggesting a lymphomagenic feed-forward regulatory loop in this pathology [25]. Consistent with those reported for other NHL subtypes, studies in BL pediatric patients, an aggressive disease characterized by reciprocal translocations of MYC with the immunoglobulin genes, found 13q31 amplification and higher levels of miR17, associated to a tendency for early relapse, confirming the importance of MYC/miR17-92 axis in lymphoma development [26,27]. Although the number miRNAs analysis in primary cutaneous lymphomas is limited, some reports have evaluated the miR-1792 cluster expression. A recent study in primary cutaneous B-cell lymphomas [28] found miR-106a (paralog), miR-20a and miR-20b over expression as well as the down regulation of PTEN (Phosphatase and tensin homolog) tumor suppressor gene associated to disease progression. Interestingly, a new study of our group [29] in patients with Mycosis Fungoides (MF), the most frequent Cutaneous T-Cell Lymphoma (CTCL), found higher levels of miR17, miR18a, miR19b and miR92a in patients compared to controls. The analysis according to morphological subtypes showed miR17 and miR-18a over expression in tumoral MF, meanwhile miR19b and mir92a exhibited increased levels in folliculotropic and transformed MFs. In addition, miRNA gene expression profiles showed that miR17 and miR19b were upregulated in patients with deletion of 9p21.3 (CDKN2A) and/or 8q24.21 (MYC) gains, providing new insights in the comprehension of MF pathobiology. In line with our results, Ralfkiaer, et al. [30] also found enhanced expression of miR-1792 paralogs, miR-106a/363 and miR-106b/25, in advanced disease compared with early MF, suggesting a role for these miRs in disease progression. Previous reports [31,32] showed that miR106b/25 is also upregulated in Sézary Syndrome, a rare and aggressive variant of CTCL, indicating a potential oncogenic function for this miR1792 paralog. In contrast Ballabio, et al. [33] found down regulation of miR17, miR19a, miR92 and miR106a in this pathology, diminishing apoptosis rates and enhancing proliferation. More studies will clarify this discordant results. Concluding, the present revision shows the important governing roles of miR-17-92 cluster and its paralogs in lymphoid malignancies. Their widespread dysregulation in these pathologies suggests they may be considered as new biomarkers that may add new insights in lymphoma diagnosis and prognosis, and also as attractive targets to design novel strategies for cancer therapy.