PLZF-RARα fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors

Abstract

Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor α (RARα). We have now cloned cDNAs encoding PLZF-RARα chimeric proteins and studied their transactivating activities. In transient- expression assays, both the PLZF(A)-RARα and PLZF(B)-RARα fusion proteins like the PML-RARα protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RARα in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RARα transactivation activity was obtained even with a very low PLZF-RARα-expressing plasmid concentration. A 'dominant negative' effect was observed when PLZF-RARα fusion proteins were cotransfected with vectors expressing RARα and retinoid X receptor α (RXRα). These abnormal transactivation properties observed in retinoic acid- sensitive myeloid cells strongly implicate the PLZF-RARα fusion proteins in the molecular pathogenesis of APL.