CSIG-32. MYC DRIVEN CANCERS ARE DEPENDENT ON CONVERGENT ONCOGENIC PATHWAYS INDUCED BY GENOMIC REARRANGEMENTS AT PVT1

Abstract

Abstract Plasmocytoma Variant Translocation 1 (PVT1) encodes a lncRNA that is co-amplified with MYC in multiple cancers. PVT1 is also a rearrangement hotspot in diverse human cancers with poor prognoses. However, the functional consequences of PVT1 rearrangement have remained obscure. Here we report that these genomic rearrangements often result in asymmetric enrichment of the proximal half of PVT1 (5’-PVT1) and loss of its distal half (3’-PVT1). Contrary to the general assumption of PVT1 being a non-coding RNA, we identified two distinct transcripts from the 5’-PVT1 and 3’-PVT1 that are capable of coding for functional peptides. A transcript from the retained 5’-PVT1 generates a circular RNA (CircPVT1) which codes for a previously unknown peptide, Firefox (FFX) with oncogenic properties. FFX can synergistically sensitize MYC and augment mTOR signaling in cancer cells. On the other hand, the 3’-PVT1 that is lost during the rearrangement, codes for a micropeptide, Honeybadger (HNB), with tumor-suppressive properties. Inhibition of HNB activates the RAS/MAPK signaling and enhances MYC stability by promoting phosphorylation of MYC Ser62. Molecular docking and biochemical analysis suggest that HNB can interfere with KRAS dimerization, implying its role as an allosteric modulator of RAS/MAPK signaling in cancer. We have previously revealed a strong selection and crucial cooperation between MYC and PVT1 in 8q24+ tumors. Moreover, breakpoints in PVT1 have led to PVT1 promoter-MYC fusions, found on ecDNA, resulting in promiscuous enhancer input to drive MYC transcription. Here we provide evidence that translocation events at the PVT1 locus can result into convergence of MYC, mTOR, and MAPK signaling. Taken together, our study nominates MYC/PVT1 amplification + PVT1 rearrangement as a major driver of cancer pathogenesis, and PVT1 as a critical node that coordinates MYC, mTOR, and MAPK activity in cancer, revealing new regulatory mechanisms that reshape the oncogenic landscape in tumors with genomic rearrangements at PVT1.