BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia
BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia
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DOI：
10.1182/blood-2010-01-264432
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发表时间：
2010-11-18
期刊：
影响因子：
20.3
通讯作者：
Emi, Nobuhiko
中科院分区：
文献类型：
--
作者：
Yamamoto, Yukiya;Tsuzuki, Sachiko;Emi, Nobuhiko
大多数急性早幼粒细胞白血病(APL)的特征是存在早幼粒细胞白血病-维甲酸受体α(RARA)融合基因。在一个很小的子集中，RARA与不同的伴侣融合，通常参与调节细胞的生长和分化。在这里，我们在APL的t(X；17)(p11；q12)变异体中发现了一个新的RARA融合转录本，BCOR-RARA，具有独特的形态特征，包括长方形和圆形细胞质包涵体。虽然患者临床上对全反式维甲酸有反应，但使用标准化疗和全反式维甲酸时出现了几次复发。BCOR是一种转录辅抑制子，通过原癌蛋白BCL6招募组蛋白去乙酰酶和多梳抑制复合体1组分。BCOR-RARA与其他RARA融合蛋白具有共同的特征。这包括：(1)RARA基因中相同的断裂点；(2)自结合；(3)维甲酸X受体α是BCOR-RARA与RARA反应元件结合所必需的；(4)对RARA转录激活的显性-负性作用；(5)异常的亚细胞重定位。值得注意的是，在45，-Y，t(X；17)(p11；q12)APL细胞中没有发现完整的BCOR，因为它们只具有重排的X染色体。这些结果更详细地强调了APL发病机制的基本特征。BCOR似乎不仅与人类先天性疾病有关，而且还与人类癌症有关。(血。2010；116(20)：4274-4283)
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. (Blood. 2010;116(20):4274-4283)