PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors

Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1178-82. doi: 10.1073/pnas.91.3.1178.

Abstract

Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor alpha (RAR alpha). We have now cloned cDNAs encoding PLZF-RAR alpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR alpha and PLZF(B)-RAR alpha fusion proteins like the PML-RAR alpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR alpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR alpha transactivation activity was obtained even with a very low PLZF-RAR alpha-expressing plasmid concentration. A "dominant negative" effect was observed when PLZF-RAR alpha fusion proteins were cotransfected with vectors expressing RAR alpha and retinoid X receptor alpha (RXR alpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Chromosomes, Human, Pair 11*
  • Chromosomes, Human, Pair 17*
  • Cloning, Molecular
  • Genetic Variation
  • Haplorhini
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / etiology
  • Leukemia, Promyelocytic, Acute / genetics*
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Receptors, Retinoic Acid / genetics*
  • Recombinant Fusion Proteins / genetics
  • Transcriptional Activation / drug effects
  • Transfection
  • Translocation, Genetic*
  • Tretinoin / pharmacology
  • Zinc Fingers / genetics

Substances

  • Neoplasm Proteins
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Tretinoin