A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies.

Abstract

Growing evidence suggests that microRNAs facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a microRNA intermediary, modulates NOTCH. MicroRNA-30a, a member of family of microRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that microRNA-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed microRNA-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression, and ultimately de-repressedmicroRNA-30a. Examination of genetic models of gain and loss of microRNA-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor suppressive role for this microRNA. Finally, the activity of the microRNA-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a microRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.