Altered ligand binding and transcriptional regulation by mutations in the PML/RAR alpha ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by a specific transloca tion, t(15;17), that fuses the promyelocytic leukemia (PML) gene with the R A receptor RAR alpha, Pharmacologic doses of retinoic acid (RA) induce diff erentiation in human APL cells and complete clinical remissions. Unfortunat ely, APL cells develop resistance to RA in vitro and in vivo. Recently, mut ations in PML/RAR alpha have been described in APL cells from patients clin ically resistant to RA therapy. The mutations cluster in 2 regions that are involved in forming the binding pocket for RA, These mutant PML/RAR alpha proteins have been expressed in vitro, which shows that they cause a divers ity of alterations in binding to ligand and to nuclear coregulators of tran scription, leading to varying degrees of inhibition of retinoid-induced tra nscription. This contrasts with the nearly complete dominant negative activ ity of mutations in PML/RAR alpha previously characterized in cell lines de veloping RA resistance in vitro. Current data from this study provide addit ional insight into the molecular mechanisms of resistance to RA and suggest that alterations in the ability of mutants to interact with coregulators c an be determinant in the molecular mechanism of resistance to RA. In partic ular, ligand-induced binding to the coactivator ACTR correlated better with transcriptional activation of RA response elements than the ligand-induced release of the corepressor SMRT. The diversity of effects that are seen in patient-derived mutations may help explain the partial success to date of attempts to overcome this mechanism of resistance in patients by the clinic al use of histone deacetylase inhibitors. (C) 2000 by The American Society of Hematology.