Year: 2026
Type: preprint
Abstract: MYC-driven (MYC + ) cancers are highly aggressive and often fatal. MYC dysregulation is a key event in these cancers, yet MYC overexpression alone is often insufficient to initiate or sustain tumorigenesis. Plasmocytoma variant translocation 1 ( PVT1 ), a long noncoding RNA (lncRNA) adjacent to MYC on chromosome 8q24, is frequently co-amplified with MYC in many of these cancers. Our prior work showed that PVT1 potentiates MYC function, although the underlying mechanism has remained unclear. Here we show that, in addition to amplification with MYC , genomic rearrangements at PVT1 frequently involve unbalanced translocations that asymmetrically enrich 5′- PVT1 while depleting 3′- PVT1 . The retained 5′- PVT1 region generates a circular RNA, CircPVT1 , that encodes a novel protein we have named Firefox (FFX). We show that FFX is essential for MYC-mediated oncogenic signaling, as its depletion markedly reduces MYC protein abundance and transcriptional output. Mechanistically, FFX stimulates AKT–mTORC1 signaling and enhances cap-dependent translational and biosynthetic capacity, thereby establishing a self-reinforcing oncogenic circuit that amplifies MYC activity. Inducible depletion of FFX in vivo significantly impairs tumor growth in MYC + xenograft models. These findings define FFX as a critical effector within the MYC - PVT1 locus and reveal a therapeutically actionable vulnerability in MYC + cancers.
Source: Genes & Development
Authors: Ashutosh Tiwari, Utkarsha Paithane, Kojiro Tashiro, Bryan Hall, Jordan Friedlein, Mayank Saraswat, Olivier Saulnier, Karina Barbosa, Quang Trinh, Shrawantee Saha, Aditi Soni, Takuma Nakashima, Rabi Murad, Svetlana Maurya, Owen S. Chapman, Brian James, Anders Erickson, Joshua T. Lange, Robyn Leary, Jyotika Varshney, Badrinath Konety, Scott M. Dehm, Yasuhiko Kawakami, David A. Largaespada, William A. Weiss, Lincoln Stein, Lukas Chavez, Hiromichi Suzuki, Sihan Wu, Jianhua Zhao, Aniruddha J. Deshpande, Michael D. Taylor, Robert J. Wechsler-Reya, Anindya Bagchi
Institutions: Sanford Burnham Prebys Medical Discovery Institute, National Cancer Institute, Jikei University School of Medicine, Inserm, Université Paris Sciences et Lettres, Hospital for Sick Children, Institut Curie, Ontario Institute for Cancer Research, National Cancer Center Research Institute, Stanford Medicine, Stanford University, University of Minnesota, Masonic Cancer Center, Rush University Medical Center, Allina Health, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Children's Medical Center, The University of Texas Southwestern Medical Center, Baylor College of Medicine, Texas Children's Hospital, Dan L Duncan Comprehensive Cancer Center, Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center
Language: English
Topic: Circular RNAs in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funders: U.S. Department of Defense, American Association for Cancer Research, American Cancer Society, Cancer Prevention and Research Institute of Texas, Gilead Sciences, Genome Canada, Government of Ontario, Government of Canada, Genome British Columbia, Cancer Research UK, National Institute for Health and Care Research, Brain Tumour Charity, Terry Fox Research Institute, National Institutes of Health, Stand Up To Cancer, Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, National Cancer Institute, DOD Prostate Cancer Research Program
Awards: G1601614885, G1935523325, G1985116395, G2061320564, G2072947043, G2166824534, G2175480743, G2292160513, G2569015222, G264098294, G2682813508, G2725826772, G2817447826, G285073136, G2944979169, G3182939611, G3294626078, Recruitment of Established Investigators, G3655805575, G3725487078, G3768254803, G3966651400, G4031651457, G4038530403, G5115508367, G521478274, Recruitment of First-Time, Tenure-Track Faculty Members, G5346823456, G5357747714, G5812395302, G6069625257, G6421542061, Functional Analysis of Low Copy Number Gain of Human 8q24 in Breast Cancer, G668039142, G7116957482, G7133393657, G7712489262, G7756677588, G7848911912, G7890600570, G7918806922, G8156467647, G8190402583, SPORE in Brain Cancer, G949115552
OpenAlex ID: W7203776243