PLZF-RAR-ALPHA 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

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 alpha (RARalpha). We have now cloned cDNAs encoding PLZF-RARalpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RARalpha and PLZF(B)-RARalpha fusion proteins like the PML-RARalpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RARalpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RARalpha transactivation activity was obtained even with a very low PLZF-RARalpha-expressing plasmid concentration. A ''dominant negative'' effect was observed when PLZF-RARalpha fusion proteins were cotransfected with vectors expressing RARalpha and retinoid X receptor alpha (RXRalpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RARalpha fusion proteins in the molecular pathogenesis of APL.