title: 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.
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 alpha (RAR alpha). We have now cloned cDNAs encoding PLZF-RAR alpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR alpha and PLZF(B)-RAR alpha fusion proteins like the PML-RAR alpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR alpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR alpha transactivation activity was obtained even with a very low PLZF-RAR alpha-expressing plasmid concentration. A "dominant negative" effect was observed when PLZF-RAR alpha fusion proteins were cotransfected with vectors expressing RAR alpha and retinoid X receptor alpha (RXR alpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL.
authors.affiliation: Shanghai Institute of Hematology, Samuel Waxman Cancer Research Foundation Laboratory of Shanghai Second Medical University, Rui-Jin Hospital, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Guidez
authors.forename: P
authors.initials: P
authors.lastname: Rousselot
authors.forename: A
authors.initials: A
authors.lastname: Agadir
authors.forename: S J
authors.initials: SJ
authors.lastname: Chen
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Degos
authors.forename: A
authors.initials: A
authors.lastname: Zelent
authors.forename: S
authors.initials: S
authors.lastname: Waxman
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D014644:Genetic Variation; D000882:Haplorhini; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014212:Tretinoin