Silencing c-Myc Using Myc Inhibitor JQ1 and EZH2 Inhibitor DZNep Blocks Converging Survival Signals in Aggressive B-Cell Lymphomas

Abstract 4618

c-Myc (hereafter Myc) overexpression has been recognized in aggressive B-cell lymphomas and linked to adverse prognosis. Myc activation results in widespread repression of miRNA expression and lymphoma aggressive progression. Our recent study identified a Myc-miRNAs-EZH2 feed-forward loop linking over-expression of Myc, EZH2, and miRNA repression. Here, using a novel small-molecule bromodomain inhibitor, JQ1, to silence Myc and the EZH2 inhibitor DZNep, we demonstrated that combined inhibition of Myc and EZH2 cooperatively disrupted Myc activation, resulting in restoration of miR-26a expression, which subsequently suppressed lymphoma growth and clonogenicity in aggressive lymphoma cells. Furthermore, Myc and EZH2 cooperatively regulated miR-26a expression in aggressive lymphoma cells. MiR-26a functioned as a tumor suppressor miRNA and mediated the combinatorial effect of JQ1 and DZNep. These findings represent a promising, novel approach for silencing Myc with JQ1 for combinatorial therapy of aggressive B-cell lymphomas.