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

Cancer Cell. 2017 May 8;31(5):697-710.e7. doi: 10.1016/j.ccell.2017.04.006.

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.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cellular Senescence*
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation
  • Gene Fusion
  • HEK293 Cells
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / genetics
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Leukemia, Promyelocytic, Acute / pathology
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Oxides / pharmacology
  • Peptides / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Stability
  • Proteolysis
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Sumoylation
  • Time Factors
  • Transfection
  • Tretinoin / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitination
  • Xenograft Model Antitumor Assays

Substances

  • Arsenicals
  • Cell Cycle Proteins
  • Oncogene Proteins, Fusion
  • Oxides
  • Peptides
  • Repressor Proteins
  • TP53 protein, human
  • TRB3 protein, mouse
  • TRIB3 protein, human
  • Tumor Suppressor Protein p53
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • Tretinoin
  • Protein Serine-Threonine Kinases
  • Arsenic Trioxide