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 r eceptor alpha (RARalpha). We have now cloned cDNAs encoding PLZF-RARal pha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RARalpha and PLZF(B)-RA Ralpha fusion proteins like the PML-RARalpha protein resulting from th e well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RARalpha in the presence of retinoic acid. Cotr ansfection assays showed that a significant repression of RARalpha tra nsactivation activity was obtained even with a very low PLZF-RARalpha- expressing plasmid concentration. A ''dominant negative'' effect was o bserved when PLZF-RARalpha fusion proteins were cotransfected with vec tors expressing RARalpha and retinoid X receptor alpha (RXRalpha). The se abnormal transactivation properties observed in retinoic acid-sensi tive myeloid cells strongly implicate the PLZF-RARalpha fusion protein s in the molecular pathogenesis of APL.