Altered nuclear cofactor switching in retinoic-resistant variants of the PML-RARα oncoprotein of acute promyelocytic leukemia

Department of Microbiology and Molecular Genetics, University of Vermont, Health Sciences Complex, Burlington, Vermont 05405, USA.
Proteins Structure Function and Bioinformatics (Impact Factor: 2.63). 04/2012; 80(4):1095-109. DOI: 10.1002/prot.24010
Source: PubMed


Acute promyelocytic leukemia (APL) results from a reciprocal translocation that fuses the gene for the PML tumor suppressor to that encoding the retinoic acid receptor alpha (RARα). The resulting PML-RARα oncogene product interferes with multiple regulatory pathways associated with myeloid differentiation, including normal PML and RARα functions. The standard treatment for APL includes anthracycline-based chemotherapeutic agents plus the RARα agonist all-trans retinoic acid (ATRA). Relapse, which is often accompanied by ATRA resistance, occurs in an appreciable frequency of treated patients. One potential mechanism suggested by model experiments featuring the selection of ATRA-resistant APL cell lines involves ATRA-resistant versions of the PML-RARα oncogene, where the relevant mutations localize to the RARα ligand-binding domain (LBD). Such mutations may act by compromising agonist binding, but other mechanisms are possible. Here, we studied the molecular consequence of ATRA resistance by use of circular dichroism, protease resistance, and fluorescence anisotropy assays employing peptides derived from the NCOR nuclear corepressor and the ACTR nuclear coactivator. The consequences of the mutations on global structure and cofactor interaction functions were assessed quantitatively, providing insights into the basis of agonist resistance. Attenuated cofactor switching and increased protease resistance represent features of the LBDs of ATRA-resistant PML-RARα, and these properties may be recapitulated in the full-length oncoproteins.

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    • ". Another work showed that failure to dissociate corepressors, or failure to recruit co-activators results in RA-resistant variants of the PML-RARα oncoprotein in APL [122]. "
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    • "However, more and more clinical observations and in vitro studies confirmed that the defects of the pathogenic fusion gene of APL, promyelocytic leukemia-retinoid acid receptorα (PML-RARα), particularly genetic mutations in the ligand binding domain (LBD) of the RARα region resulting in deficient ATRA binding was the major cause of ATRA resistance6789101112131415. Furthermore, altered ligand-induced co-repressor release, co-activator recruitment and impaired transcriptional activation of genes with the retinoic acid response elements (RAREs) sites were associated with ATRA resistance1617. Besides PML-RARα, mutations in other genes, such as FLT3-ITD or TP53 might also contribute to ATRA resistance1819. "
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    ABSTRACT: All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In ATRA resistant APL cell lines NB4-R1 and NB4-R2, the combination of staurosporine and ATRA synergized to trigger differentiation accompanied by significantly enhanced protein level of CCAAT/enhancer binding protein ε (C/EBPε) and C/EBPβ as well as the phosphorylation of mitogen-activated protein (MEK) and extracellular signal-regulated kinase (ERK). Furthermore, attenuation of the MEK activation blocked not only the differentiation but also the increased protein level of C/EBPε and C/EBPβ. Taken together, we concluded that the combination of ATRA and staurosporine could overcome differentiation block via MEK/ERK signaling pathway in ATRA-resistant APL cell lines.
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