Overexpression of Wild-Type Retinoic Acid Receptor  (RAR) Recapitulates Retinoic Acid-Sensitive Transformation of Primary Myeloid Progenitors by Acute Promyelocytic Leukemia RAR-Fusion Genes

Abstract

Retinoic acid receptor  (RAR) is the target of several chromosomal translocations associated with acute promyelocytic leukemias (APLs). These rearrangements fuse RAR to different partner genes creating the chimeric proteins: PML-RAR, PLZF-RAR, and NPM-RAR. Although the vast majority of APLs respond to retinoic acid therapy, those associated with PLZF-RAR are resistant. We have used retroviruses to express PML-RAR, PLZF-RAR, NPM-RAR, RAR403 (a dominant negative mutant of RAR), and wild-type RAR in murine bone marrow progenitors and found that all of these constructs blocked differentiation and led to the immortalization of myeloid progenitors. This cellular transformation is specific to an alteration of the RAR pathway because overexpression of RARβ, RARγ, or RXR did not result in similar growth perturbations. Pharmacological doses of RA induced differentiation and inhibited proliferation of cells transformed with either of the APL fusion genes, including PLZF-RAR, whereas physiological retinoic acid concentrations were sufficient to reverse the phenotype of cells transformed with wild-type RAR. The cellular responses to retinoic acid were accompanied by a sharp decrease in the amount of the RAR-fusion proteins expressed in the cells. Our findings suggest that the oncogenicity of RAR-fusion proteins results from their nature to behave as unliganded RAR in the presence of physiological concentrations of retinoic acid.