Koken M H, Puvion-Dutilleul F, Guillemin M C, Viron A, Linares-Cruz G, Stuurman N, de Jong L, Szostecki C, Calvo F, Chomienne C
CNRS UPR 43, Centre Hayem, Hôpital St Louis, Paris, France.
EMBO J. 1994 Mar 1;13(5):1073-83. doi: 10.1002/j.1460-2075.1994.tb06356.x.
Nuclear bodies (NBs) are ultrastructurally defined granules predominantly found in dividing cells. Here we show that PML, a protein involved in the t(15;17) translocation of acute promyelocytic leukaemia (APL), is specifically bound to a NB. PML and several NB-associated proteins, found as auto-antigens in primary biliary cirrhosis (PBC), are co-localized and co-regulated. The APL-derived PML-RAR alpha fusion protein is shown to be predominantly localized in the cytoplasm, whereas a fraction is nuclear and delocalizes the NB antigens to multiple smaller nuclear clusters devoid of ultrastructural organization. RA administration (which in APL patients induces blast differentiation and consequently complete remissions) causes the re-aggregation of PML and PBC auto-antigens onto the NB, while PML-RAR alpha remains mainly cytoplasmic. Thus, PML-RAR alpha expression leads to a RA-reversible alteration of a nuclear domain. These results shed a new light on the pathogenesis of APL and provide a molecular link between NBs and oncogenesis.
核体（NBs）是在超微结构上定义的颗粒，主要存在于分裂细胞中。我们在此表明，参与急性早幼粒细胞白血病（APL）t(15;17)易位的蛋白质PML特异性地与一个核体结合。PML和几种在原发性胆汁性肝硬化（PBC）中作为自身抗原发现的与核体相关的蛋白质共定位且共同调控。源自APL的PML-RARα融合蛋白主要定位于细胞质，而一部分定位于细胞核并将核体抗原分散至多个无超微结构组织的较小核簇。给予维甲酸（RA，在APL患者中可诱导原始细胞分化并最终实现完全缓解）会使PML和PBC自身抗原重新聚集到核体上，而PML-RARα仍主要位于细胞质中。因此，PML-RARα的表达导致核结构域发生RA可逆性改变。这些结果为APL的发病机制提供了新的线索，并在核体与肿瘤发生之间建立了分子联系。
