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

• DOI: 10.1016/j.ccell.2017.04.006
• Publication Date: 2017-05-08T16:32:39Z
• Authors: Ke Li; Feng Wang; Wen-Bin Cao; Xiao-Xi Lv; Fang Hua; Bing Cui; Jiao-Jiao Yu; Xiao-Wei Zhang; Shuang Shang; Shan-Shan Liu; Jin-Mei Yu; Ming-Zhe Han; Bo Huang; Ting-Ting Zhang; Xia Li; Jian-Dong Jiang; Zhuo-Wei Hu
• Keywords: Arsenic Trioxide; Promyelocytic leukemia protein; Tretinoin; Senescence

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.