Abstract A39: The mitochondrial translation machinery is a critical effector of Myc in lymphomagenesis

Abstract

Abstract The Myc protein, encoded by the c-myc proto-oncogene, is a transcription factor that binds thousands of genomic loci. Based on genome-wide binding and expression profiles, we recently provided an exhaustive list of genes that are up- or down-regulated by Myc during B-cell lymphomagenesis in Eµ-myc transgenic mice (Sabò et al. 2014 Nature 511, 488-492). Which among those Myc-regulated genes are critical effectors in tumor progression and maintenance remained largely unknown. Here, we show that concerted activation by Myc of the mitochondrial translation machinery is critical for the maintenance of Myc-induced lymphomas. A majority of genes encoding for Mitochondrial Ribosomal Proteins (MRPs) and other associated polypeptides were directly up-regulated by Myc in Eµ-myc lymphomas. Among those was the gene encoding PTCD3, a Pentatricopeptide repeat protein involved in mitochondrial translation (Davies et al. 2009 FEBS Lett. 583, 1853-1858). RNAi-based knockdown of PTCD3 or several MRPs conferred a selective disadvantage in lymphoma cells, owing to impaired cell proliferation. As expected PTCD3 knockdown in lymphomas was also accompanied by a reduction in the levels of mitochondrial-encoded protein COX-I. Chemical inhibition of mitochondrial translation with Tigecycline led to rapid death of Eµ-myc lymphoma cells in vitro. We are currently testing the effect of Tigecycline on lymphoma growth in vivo. Citation Format: Aleco D'Andrea, Valerio Bianchi, Paola Nicoli, Bruno Amati. The mitochondrial translation machinery is a critical effector of Myc in lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A39.