TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence
TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence
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TRIB3 通过稳定癌蛋白 PML-RAR α 和抑制 p53 介导的衰老来促进 APL 进展
DOI：
10.1016/j.ccell.2017.04.006
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发表时间：
2017-05-08
期刊：
影响因子：
50.3
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Li, Ke;Wang, Feng;Hu, Zhuo-Wei
急性早幼粒细胞白血病(APL)是由癌蛋白PML-RARα驱动的，它拮抗髓系分化，促进APL启动的细胞自我更新。全反式维甲酸(ATRA)联合三氧化二砷(As2O3)或化疗可显著改善APL患者的预后。在此，我们报道了假性蛋白激酶Tribble 3(TRIB3)的表达与APL的进展和治疗耐药呈正相关。上调的TRIB3表达通过与PML-RARα相互作用并抑制其总甲基化、泛素化和降解来促进APL。这抑制了PML核体组装、P53介导的衰老和细胞分化，并支持细胞自我更新。通过基因抑制TRIB3的表达或干扰TRIB3/PML-RARα与ATRA/As_2O_3相互作用的肽的组合，通过加速PML-RARα的降解来根除APL。我们的研究为APL的发病机制提供了洞察力，并为APL提供了一种潜在的治疗选择。
Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RAR alpha, 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-RAR alpha 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-RAR alpha interaction with ATRA/As2O3 eradicates APL by accelerating PML-RAR alpha degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL.