Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia

Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RAR alpha 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 PLZF-RAR alpha fusion protein. Both PML-and PLZF-RAR alpha 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 RAR alpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RAR alpha, it had a very little effect on its association with the PLZF-RAR alpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RAR alpha 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-RAR alpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RAR alpha 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 PML-and PLZF-RAR alpha-associated leukemias to ATRA. (C) 1998 by The American Society of Hematology.