Cancer Cell 31:697(2017)

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

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


摘要:

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARa, 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-RARa 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-RARa interaction with ATRA/As2O3 eradicates APL by accelerating PML-RARa degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL.

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