title: BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia.
abstract: 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.
authors.affiliation: Department of Hematology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan. yyukiya@fujita-hu.ac.jp
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsuzuki
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tsuzuki
authors.forename: Kousuke
authors.initials: K
authors.lastname: Handa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Inaguma
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Emi
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014178:Translocation, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C084103:BCL6 protein, human; C411984:BCOR protein, human; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C000607071:RARA protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin