Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARalpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient

Oncogene. 1999 Jan 28;18(4):1113-8. doi: 10.1038/sj.onc.1202414.

Abstract

Primary blasts of a t(11;17)(q23;q21) acute promyelocytic leukaemia (APL) patient were analysed with respect to retinoic acid (RA) and arsenic trioxide (As2O3) sensitivity as well as PLZF/RARalpha status. Although RA induced partial monocytic differentiation ex vivo, but not in vivo, As203 failed to induce apoptosis in culture, contrasting with t(15;17) APL and arguing against the clinical use of As203 in t(11;17)(q23;q21) APL. Prior to cell culture, PLZF/RARalpha was found to exactly co-localize with PML onto PML nuclear bodies. However upon cell culture, it quickly shifted towards microspeckles, its localization found in transfection experiments. Arsenic trioxide, known to induce aggregation of PML nuclear bodies, left the microspeckled PLZF/RARalpha localization completely unaffected. RA treatment led to PLZF/RARalpha degradation. However, this complete PLZF/RARalpha degradation was not accompanied by differentiation or apoptosis, which could suggest a contribution of the reciprocal RARalpha/PLZF fusion product in leukaemogenesis or the existence of irreversible changes induced by the chimera.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Blotting, Western
  • Cell Differentiation / drug effects
  • Chromosomes, Human, Pair 11
  • Chromosomes, Human, Pair 17
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm
  • Fluorescent Antibody Technique
  • Humans
  • Kruppel-Like Transcription Factors
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / genetics
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Leukemia, Promyelocytic, Acute / pathology
  • Oncogene Proteins, Fusion / drug effects*
  • Oncogene Proteins, Fusion / metabolism
  • Oxides / pharmacology*
  • Promyelocytic Leukemia Zinc Finger Protein
  • Receptors, Retinoic Acid / drug effects*
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Transcription Factors / drug effects*
  • Transcription Factors / metabolism
  • Translocation, Genetic
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured / drug effects

Substances

  • Antineoplastic Agents
  • Arsenicals
  • DNA-Binding Proteins
  • Kruppel-Like Transcription Factors
  • Oncogene Proteins, Fusion
  • Oxides
  • Promyelocytic Leukemia Zinc Finger Protein
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Transcription Factors
  • ZBTB16 protein, human
  • Tretinoin
  • Arsenic Trioxide