Paithane, Utkarsha, Tiwari, Ashutosh, Hall, Bryan, Tashiro, Kojiro, Saulnier, Olivier, Trinh, Quang, Soni, Aditi, Nakashima, Takuma, Bobkov, Andrey A, Fujimoto, Lynn Miya, Saraswat, Mayank, Sarmashghi, Shahab, Hendrikse, Liam D, Masihi, Meher Beigi, Saha, Shrawantee, Ghosh, Srija, James, Brian, Erickson, Anders, Eisemann, Tanja, Tzaridis, Theophilos, Konety, Badrinath, Dehm, Scott M, Beroukhim, Rameen, Chavez, Lukas, Largaespada, David A, Stein, Lincoln, Suzuki, Hiromichi, Weiss, William A, Yeh, Johannes, Zhao, Jianhua, Wechsler-Reya, Robert J, Taylor, Michael D, Bagchi, Anindya (August 2026) Honeybadger, a micropeptide encoded by an alternative PVT1 transcript, is a critical negative regulator of RAS-MAPK signaling in MYC-driven tumors. Genes & Development. ISSN 0890-9369
Abstract
Genomic rearrangements can drive cancer through mechanisms that extend beyond classical oncogenic fusions such as BCR-ABL A substantial fraction of these events involve long noncoding RNAs (lncRNAs), yet their functional impact on tumorigenesis has remained largely opaque. The lncRNA plasmacytoma variant translocation 1 (PVT1), positioned adjacent to MYC at chromosome 8q24, is among the most frequently altered loci in MYC-driven (MYC+) cancers. We recently showed that PVT1 translocations produce a characteristic asymmetric architecture that preserves the 5'-PVT1 region, generating a circular RNA (CircPVT1) that encodes Firefox (FFX), a novel oncoprotein that activates AKT-mTORC1 signaling and cooperates with MYC. Here, we uncover a complementary and opposing function for the deleted 3'-PVT1 segment, which encodes a tumor-suppressive micropeptide we term Honeybadger (HNB). HNB binds KRAS and dampens RAS-MAPK signaling, and its loss derepresses this pathway and stabilizes MYC via Ser62 phosphorylation. Thus, a single class of structural alterations at PVT1 simultaneously installs FFX-mediated AKT-mTORC1 activation and removes HNB-mediated RAS-MAPK regulation, creating a dual mechanism that synergistically amplifies MYC output. This oncoprotein gain coupled with tumor-suppressor loss provides a mechanistic explanation for the particularly poor prognosis of PVT1-rearranged cancers and establishes PVT1 as a central regulatory hub in MYC+ malignancies.
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