PLZF-RARα Fusion Proteins Generated from the Variant t(11;17)(q23;q 21) Translocation in Acute Promyelocytic Leukemia Inhibit Ligand-Dependent Transactivation of Wild-Type Retinoic Acid Receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS 1994-02, Vol.91 (3), p.1178-1182
• Main Authors: Chen, Zhu, Guidez, Fabien, Rousselot, Philippe, Agadir, Annissa, Chen, Sai-Juan, Wang, Zhen-Yi, Degos, Laurent, Zelent, Arthur, Waxman, Samuel, Chomienne, Christine
• Format: Article
• Language: English
• Subjects: acute promyeloid leukemia; Amino Acid Sequence; Animals; cDNA; Cell Line; chimeras; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 17; Cloning, Molecular; COS cells; fusion protein; Genes; Genetic Variation; Genetic vectors; Haplorhini; Humans; inhibition; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - etiology; Leukemia, Promyelocytic, Acute - genetics; man; Molecular Sequence Data; Myeloid cells; Neoplasm Proteins - genetics; Plasmids; PLZF gene; Protein isoforms; RAR alpha gene; Receptors; Receptors, Retinoic Acid - genetics; Recombinant Fusion Proteins - genetics; Reporter genes; retinoic acid; Transactivation; Transcriptional Activation - drug effects; Transfection; Translocation, Genetic; Tretinoin - pharmacology; Zinc; zinc finger; Zinc Fingers - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.3.1178

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.