Formation of PML/RARα high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RARα-mediated retinoic acid response

Publisher Website
Google Scholar
Abstract
Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukaemia (APL) patients by triggering terminal differentiation of neoplastic cells. RA-sensitivity in APL is mediated by its oncogenic protein, which results from the recombination of the PML and the RA receptor α (RARα) genes (PML/RARα fusion protein). Ectopic expression of PML/RARα into haemopoietic cell lines results in increased response to RA-induced differentiation. By structure-function analysis of PML/RARα-mediated RA-differentiation, we demonstrated that fusion of PML and RARα sequences and integrity of the PML dimerization domain and of the RARα DNA binding region are required for the effect of PML/RARα on RA-differentiation. Indeed, direct fusion of the PML dimerization domain to the N- or C-terminal extremities of RARα retained full biological activity. All the biologically active PML/RARα mutants formed high molecular weight complexes in vivo. Functional analysis of mutations within the PML dimerization domain revealed that the capacity to form PML/RARα homodimers, but not PML/RARα-PML heterodimers, correlated with the RA-response. These results suggest that targeting of RARα sequences by the PML dimerization domain and formation of nuclear PML/RARα homodimeric complexes are crucial for the ability of PML/RARα to mediate RA-response.