SPECIAL FOCUS Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor Binding to PML- and PLZF-RARa Underlie Molecular Pathogenesis and Treatment of Acute Promyelocytic Leukemia

Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARa fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZFRARa fusion protein. Both PMLand PLZF-RARa possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARa protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARa, it had a very little effect on its association with the PLZF-RARa fusion protein. This ATRAinsensitive interaction between N-CoR and PLZF-RARa was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARa fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARa on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/ histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PMLand PLZF-RARa–associated leukemias to ATRA. r 1998 by The American Society of Hematology.