Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia.
Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic 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-RARalpha fusion protein. Both PML- and PLZF-RARalpha 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 RARalpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARalpha, it had a very little effect on its association with the PLZF-RARalpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha 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-RARalpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARalpha 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-RARalpha-associated leukemias to ATRA.
Mesh Terms:
Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Leukemia, Promyelocytic, Acute, Neoplasm Proteins, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Oncogene Proteins, Fusion, Protein Binding, Repressor Proteins, Transcription Factors, Translocation, Genetic, Tretinoin, Tumor Cells, Cultured, Zinc Fingers
Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Leukemia, Promyelocytic, Acute, Neoplasm Proteins, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Oncogene Proteins, Fusion, Protein Binding, Repressor Proteins, Transcription Factors, Translocation, Genetic, Tretinoin, Tumor Cells, Cultured, Zinc Fingers
Blood
Date: Apr. 15, 1998
PubMed ID: 9531570
View in: Pubmed Google Scholar
Download Curated Data For This Publication
9816
Switch View:
- Interactions 3