Epigenetics, c-Myc and Aggressive B-cell Lymphomas

c-Myc (hereafter referred to as Myc) protein plays a fundamental role in cell cycle regulation, proliferation, differentiation, and apoptosis by modulating the expression of a large number of targets [1]. Expression of Myc is frequently deregulated in human cancers and is often associated with aggressive disease. In non-Hodgkin lymphomas, although Myc has been described as a defining feature and the driving oncogene for Burkitt lymphoma, Myc overexpression has also been recognized in other aggressive B-cell lymphomas and has been linked to adverse prognosis [2]. In addition to Burkitt lymphoma, these aggressive lymphomas include Myc-associated diffuse large B-cell lymphoma (DLBCL), double-hit lymphoma, acute lymphoblastic lymphoma, a blastic variant of mantle cell lymphoma (MCL), transformed follicular lymphoma, and plasmablastic lymphoma. However, mechanisms underlying the sustained activation of Myc and subsequent contribution to clinical fatality are unclear. Recently, Myc transcriptional network has been shown to also include microRNAs [3]. These small non-protein-coding, single-stranded RNAs function as negative regulators of mRNA and affect virtually every aspect of tumorigenesis [3]. Although Myc can alter a large set of miRNAs, rather than activation, the majority of identified miRNAs are repressed by Myc [4]. Among these repressed miRNAs, many are putative tumor suppressors, such as let-7, miR-15a/16-1, miR-26a, miR-29, and miR-34a. Each of these miRNAs has been associated with anti-proliferative, pro-apoptotic, and/or anti-tumorigenic activity. Reactivating these miRNAs in Myc-transformed B lymphoma cell lines dramatically inhibits tumorigenesis [4], indicating that reconstituting lymphoma with these tumor suppressor miRNAs could be therapeutically beneficial in Myc-associated lymphomas. Therefore, it is likely that Myc hyperactivity contributes to widespread repression of miRNA expression and that Myc-driven miRNA repression underlies the molecular mechanisms related to lymphoma aggressive transformation. We recently explored the role of epigenetic regulation in Myc-mediated miRNA repression [5]. We revealed 1) loss or low expression of c-Myc-regulated miRNAs in aggressive B-cell lymphomas; 2) reverse correlation of tumor suppressor miRNAs such as miR-26a and miR29-a-c with Myc as well as cell proliferation, CDK6, and IGF-1R expression; 3) ectopic expression of miR-26a, miR-29 suppression of CDK-6, and IGF-1R and Myc-driven cell proliferation in aggressive lymphoma cell lines and primary lymphomas; and 4) miR-26a and miR-29 repression as a result of Myc/HDAC3 and EZH2 (a catalytic component of polycomb repressive complex 2, PRC2) interaction. Results of these studies have led to the identification of a novel model for interplay between Myc, HDAC3, PRC2, and miRNAs and their contribution to Myc-associated lymphomagenesis, and HDAC3/EZH2/miRNAs as …