Interaction with RXR is necessary for NPM-RAR-induced myeloid differentiation blockade

Leuk Res. 2013 Dec;37(12):1704-10. doi: 10.1016/j.leukres.2013.09.024. Epub 2013 Sep 29.

Abstract

The t(5;17)(q35;q21) APL variant results in expression of a fusion protein linking the N-terminus of nucleophosmin (NPM) to the C-terminus of the retinoic acid receptor alpha (RAR). We have previously shown that NPM-RAR is capable of binding to DNA either as a homodimer or heterodimer with RXR. To determine the biological significance of NPM-RAR/RXR interaction, we developed two mutants of NPM-RAR that showed markedly diminished ability to bind RXR. U937 subclones expressing the NPM-RAR mutants showed significantly less inhibition of vitamin D3/TGFbeta-induced differentiation, compared with NPM-RAR. These results support the hypothesis that RXR interaction is necessary for NPM-RAR-mediated myeloid maturation arrest.

Keywords: Acute promyelocytic leukemia; Differentiation; NPM-RAR; RXR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • COS Cells
  • Cell Differentiation*
  • Chlorocebus aethiops
  • Down-Regulation
  • Humans
  • Myeloid Cells / physiology*
  • Oncogene Proteins, Fusion / physiology*
  • Protein Binding / physiology
  • Protein Multimerization / physiology
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors / metabolism*
  • U937 Cells

Substances

  • NPM-RARalpha protein, human
  • Oncogene Proteins, Fusion
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptors