Lavau C, Dejean A
Dept des Rétrovirus, INSERM U. 163, Institut Pasteur, France.
Leukemia. 1994 Oct;8(10):1615-21.
Acute promyelocytic leukemia is characterized by a specific t(15;17) chromosomal translocation and a particular sensitivity to retinoic acid. The translocation fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene resulting in the production of a PML-RAR alpha fusion protein. The hybrid molecule retains most of the functional domains of both native products, PML and RAR alpha, but it has novel features. Its cellular distribution is completely reorganized when compared to that of PML: the hybrid is found in multiple small nuclear substructures and upon retinoic acid treatment, it goes back to the normal PML localization, that is in typical well organized nuclear bodies. PML-RAR alpha also acquires novel transcriptional properties if compared to RAR alpha, it does so either by direct binding to target gene regulatory sequences or by protein interaction with cofactors. Expression of PML-RAR alpha in HL60 or U937 cell has been shown to block their maturation while it can force their differentiation at high doses of retinoic acid. Different mechanisms are proposed to explain how PML-RAR alpha blocks differentiation and how this may be reversed by retinoic acid. A likely hypothesis might be the delocalization of critical cofactors into the aberrant PML-RAR alpha substructures while the therapeutic effect of retinoic acid would be correlated to its capacity to restore a normal nuclear organization.
急性早幼粒细胞白血病的特征是存在特定的t(15;17)染色体易位以及对维甲酸具有特殊敏感性。这种易位使早幼粒细胞白血病基因（PML）与维甲酸受体α（RARα）基因融合，导致产生PML-RARα融合蛋白。该杂合分子保留了天然产物PML和RARα的大部分功能结构域，但具有新的特性。与PML相比，其细胞分布完全重新组织：杂合体存在于多个小的核亚结构中，在维甲酸处理后，它会回到正常的PML定位，即在典型的结构良好的核体中。与RARα相比，PML-RARα也获得了新的转录特性，它通过直接结合靶基因调控序列或与辅因子进行蛋白质相互作用来实现。已证明在HL60或U937细胞中表达PML-RARα会阻止它们的成熟，而在高剂量维甲酸作用下可促使它们分化。人们提出了不同的机制来解释PML-RARα如何阻断分化以及维甲酸如何逆转这种情况。一个可能的假说是关键辅因子被重新定位到异常的PML-RARα亚结构中，而维甲酸的治疗效果与其恢复正常核组织的能力相关。
