TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated 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.
Mesh Terms:
Animals, Antineoplastic Combined Chemotherapy Protocols, Arsenicals, Cell Cycle Proteins, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cellular Senescence, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Gene Fusion, HEK293 Cells, Humans, Leukemia, Promyelocytic, Acute, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Oncogene Proteins, Fusion, Oxides, Peptides, Protein Stability, Protein-Serine-Threonine Kinases, Proteolysis, Repressor Proteins, Signal Transduction, Sumoylation, Time Factors, Transfection, Tretinoin, Tumor Suppressor Protein p53, Ubiquitination, Xenograft Model Antitumor Assays
Animals, Antineoplastic Combined Chemotherapy Protocols, Arsenicals, Cell Cycle Proteins, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cellular Senescence, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Gene Fusion, HEK293 Cells, Humans, Leukemia, Promyelocytic, Acute, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Oncogene Proteins, Fusion, Oxides, Peptides, Protein Stability, Protein-Serine-Threonine Kinases, Proteolysis, Repressor Proteins, Signal Transduction, Sumoylation, Time Factors, Transfection, Tretinoin, Tumor Suppressor Protein p53, Ubiquitination, Xenograft Model Antitumor Assays
Cancer Cell
Date: Dec. 08, 2016
PubMed ID: 28486108
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