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.