TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence

Abstract

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which antagonizes myeloid differentiation and promotes APL-initiating cell self-renewal. Combined all-trans retinoic acid (ATRA) with arsenic trioxide (As₂O₃) or chemotherapy dramatically improves the prognosis of APL patients. Here we report that expression of pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARα and suppressing its sumoylation, ubiquitylation, and degradation. This represses PML nuclear body assembly, p53-mediated senescence, and cell differentiation, and supports cellular self-renewal. Genetically inhibiting TRIB3 expression or combination of a peptide disturbing TRIB3/PML-RARα interaction with ATRA/As₂O₃ eradicates APL by accelerating PML-RARα degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL.

Keywords: AML; UPS; cell differentiation; leukemia-initiating cells; protein quality control; protein-protein interaction; psuedokinase; sumoylation; tribbles.