Abstract
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.
Keywords:
AML; UPS; cell differentiation; leukemia-initiating cells; protein quality control; protein-protein interaction; psuedokinase; sumoylation; tribbles.
Copyright © 2017 Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Arsenic Trioxide
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Arsenicals / pharmacology
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Cell Cycle Proteins / deficiency
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation*
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Cellular Senescence*
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Disease Progression
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Drug Resistance, Neoplasm
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Female
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Gene Expression Regulation
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Gene Fusion
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HEK293 Cells
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Humans
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Leukemia, Promyelocytic, Acute / drug therapy
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / metabolism*
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Leukemia, Promyelocytic, Acute / pathology
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Male
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Oxides / pharmacology
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Peptides / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Stability
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Proteolysis
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Sumoylation
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Time Factors
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Transfection
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Tretinoin / pharmacology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitination
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Xenograft Model Antitumor Assays
Substances
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Arsenicals
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Cell Cycle Proteins
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Oncogene Proteins, Fusion
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Oxides
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Peptides
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Repressor Proteins
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TP53 protein, human
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TRB3 protein, mouse
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TRIB3 protein, human
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Tumor Suppressor Protein p53
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Tretinoin
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Protein Serine-Threonine Kinases
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Arsenic Trioxide