Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor Binding to PML- and PLZF-RARα Underlie Molecular Pathogenesis and Treatment of Acute Promyelocytic Leukemia

• Published in: Blood Vol. 91; no. 8; pp. 2634 - 2642
• Main Authors: Guidez, Fabien, Ivins, Sarah, Zhu, Jun, Söderström, Mats, Waxman, Samuel, Zelent, Arthur
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.1998; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Antineoplastic agent; Human; Promyelocytic leukemia; Acyltransferases; Nuclear receptor; Enzyme; Pathogenesis; Zinc finger structure; Transferases; Acute; Cytotoxicity; Molecular interaction; Malignant hemopathy; Retinoids; Histone acetyltransferase; Transfection; Established cell line; Alpha-Peptide chain; Fusion protein; Retinoic acid; Biological receptor; Tretinoin
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V91.8.2634.2634_2634_2642

Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all-transretinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it had a very little effect on its association with the PLZF-RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα–associated leukemias to ATRA.