Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China.
Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China.
Cancer Cell. 2017 May 8;31(5):697-710.e7. doi: 10.1016/j.ccell.2017.04.006.
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 (AsO) 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/AsO eradicates APL by accelerating PML-RARα degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL.
急性早幼粒细胞白血病（APL）由癌蛋白 PML-RARα驱动，该蛋白拮抗髓系分化并促进 APL 起始细胞自我更新。联合全反式维甲酸（ATRA）与三氧化二砷（AsO）或化疗可显著改善 APL 患者的预后。本研究报道，拟激酶 Tribble 3（TRIB3）的表达与 APL 的进展和治疗耐药性呈正相关。升高的 TRIB3 表达通过与 PML-RARα相互作用并抑制其 sumoylation、泛素化和降解来促进 APL。这抑制了 PML 核体的组装、p53 介导的衰老和细胞分化，并支持细胞自我更新。遗传抑制 TRIB3 表达或用干扰 TRIB3/PML-RARα 相互作用的肽与 ATRA/AsO 联合使用可通过加速 PML-RARα 降解来根除 APL。本研究为 APL 的发病机制提供了深入了解，并为对抗 APL 提供了一种潜在的治疗选择。
