Forced retinoic acid receptor alpha homodimers prime mice for APL-like leukemia

Cancer Cell. 2006 Feb;9(2):81-94. doi: 10.1016/j.ccr.2005.12.030.

Abstract

RARA becomes an acute promyelocytic leukemia (APL) oncogene by fusion with any of five translocation partners. Unlike RARalpha, the fusion proteins homodimerize, which may be central to oncogenic activation. This model was tested by replacing PML with dimerization domains from p50NFkappaB (p50-RARalpha) or the rapamycin-sensitive dimerizing peptide of FKBP12 (F3-RARalpha). The X-RARalpha fusions recapitulated in vitro activities of PML-RARalpha. For F3-RARalpha, these properties were rapamycin sensitive. Although in vivo the artificial fusions alone are poor initiators of leukemia, p50-RARalpha readily cooperates with an activated mutant CDw131 to induce APL-like disease. These results demonstrate that the dimerization interface of RARalpha fusion partners is a critical element in APL pathogenesis while pointing to other features of PML for enhancing penetrance and progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / pathology
  • Carcinogens / metabolism
  • Cell Line
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Down-Regulation / genetics
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Leukemia, Promyelocytic, Acute / pathology*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Neoplasm Proteins / metabolism
  • Oncogene Proteins, Fusion / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • Receptors, Cytokine / metabolism
  • Receptors, Retinoic Acid / chemistry*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors / metabolism
  • Transcription, Genetic / genetics

Substances

  • Carcinogens
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Rara protein, mouse
  • Receptors, Cytokine
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • DNA