Weis K, Rambaud S, Lavau C, Jansen J, Carvalho T, Carmo-Fonseca M, Lamond A, Dejean A
European Molecular Biology Laboratory, Heidelberg Federal Republic of Germany.
Cell. 1994 Jan 28;76(2):345-56. doi: 10.1016/0092-8674(94)90341-7.
Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) translocation that fuses the retinoic acid receptor alpha (RAR alpha) to a novel gene product, PML. The involvement of RAR alpha is particularly intriguing in view of the efficient therapeutic effect of retinoic acid (RA) in this disease. In this report, we show that PML is specifically localized within a discrete subnuclear compartment corresponding to nuclear bodies recognized by patient autoimmune sera. In APL cells, the PML-RAR alpha hybrid displays an abnormal localization and directs RXR and other nuclear antigens into aberrant structures that are tightly bound to chromatin. This suggests that the hybrid could exert a dominant negative effect by diverting a subset of proteins from their natural sites of action. Interestingly, treatment of APL cells with RA induces a complete relocalization of each of these proteins. We propose that the beneficial role of RA in promoting myeloid differentiation in APL might be related to its ability to restore a normal subnuclear organization.
急性早幼粒细胞白血病（APL）的特征是存在一种特异性的t(15;17)易位，该易位使维甲酸受体α（RARα）与一种新的基因产物PML融合。鉴于维甲酸（RA）对这种疾病具有有效的治疗作用，RARα的参与尤其引人关注。在本报告中，我们表明PML特异性定位于一个离散的核内区室，该区域对应于患者自身免疫血清识别的核小体。在APL细胞中，PML-RARα融合蛋白表现出异常定位，并将RXR和其他核抗原导向与染色质紧密结合的异常结构。这表明该融合蛋白可能通过将一部分蛋白质从其天然作用位点转移而发挥显性负效应。有趣的是，用RA处理APL细胞会导致这些蛋白质中的每一种都发生完全的重新定位。我们提出，RA在促进APL中髓系分化方面的有益作用可能与其恢复正常核内亚结构组织的能力有关。
