BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia.
The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a promyelocytic leukemia-retinoic acid receptor alpha(RARA) fusion gene. In a small subset, RARA is fused to a different partner, usually involved in regulating cell growth and differentiation. Here, we identified a novel RARA fusion transcript, BCOR-RARA, in a t(X;17)(p11;q12) variant of APL with unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. Although the patient was clinically responsive to all-trans retinoic acid, several relapses occurred with standard chemotherapy and all-trans retinoic acid. BCOR is a transcriptional corepressor through the proto-oncoprotein, BCL6, recruiting histone deacetylases and polycomb repressive complex 1 components. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (1) the same break point in RARA cDNA; (2) self-association; (3) retinoid X receptor alpha is necessary for BCOR-RARA to associate with the RARA responsive element; (4) action in a dominant-negative manner on RARA transcriptional activation; and (5) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged X chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases, but also in a human cancer.
Pubmed ID: 20807888 RIS Download
Base Sequence | Cell Line, Tumor | Chromosomes, Human, Pair 17 | Chromosomes, Human, X | Cloning, Molecular | DNA-Binding Proteins | Genes, Dominant | Humans | Leukemia, Promyelocytic, Acute | Male | Middle Aged | Molecular Sequence Data | Oncogene Proteins, Fusion | Protein Binding | Protein Transport | Proto-Oncogene Proteins | RNA, Messenger | Receptors, Retinoic Acid | Repressor Proteins | Response Elements | Subcellular Fractions | Transcriptional Activation | Translocation, Genetic | Tretinoin