维甲酸与急性早幼粒细胞白血病(APL)

RA and acute promyelocytic leukaemia(APL)

维甲酸(retinoic acid,RA)为维生素A的衍生物,它在生长控制、上皮分化、胚胎发育等方面发挥主要功能。维甲酸受体RARs(retinoic acid receptors)及RXRs(retinoid X receptors)是类似于类固醇激素受体和甲状腺素受体的一类核受体,它是一种依赖于激素活化的转录因子,能以RAR/RXR异二聚体的形式结合在目的基因的启动子上,抑制或活化转录过程,该过程受激素控制。染色体的易位促使早幼粒白血病(pro-myelocytic leukemia,PML)基因和RARα的编码基因相结合,表达PML/RARα融合蛋白并最终导致急性早幼粒细胞白血病(APL)的发生。维甲酸处理后,APL细胞在体内或体外表现发生了极大的改变(APL细胞停止了恶性分裂,经历了类似HL60细胞和F9细胞的终端分化)。同时,APL也对三氧化二砷(As2O3)非常敏感,维甲酸和As2O3都可以直接作用于PML/RARα融合蛋白。正因为如此,APL细胞成为了分化治疗及癌基因靶向治疗的首例。本文重点综述了APL发生的机制及维甲酸治疗APL的进展。

Retinoic acids（RA） are vitamin A derivatives that exert major effects on growth control,epithelial differentiation and embryonic development.Retinoic acid receptors（RARs） and retinoid X receptors（RXRs） are nuclear receptors,like those for steroids or thyroid hormones.They are hormone-activated transcription factors that bind to the promoters of their target genes as RAR/RXR heterodimers and repress or activate their transcription depending on the presence of hormone.A chromosome translocation fuses the PML gene to that of RARa,creating a PML/RARa fusion protein and resulting in the occurrence of acute promyelocytic leukemia（APL）.After RA treatment,APL cells undergo terminal differentiation ex vivo or in vivo,similar to HL60 or F9 cells.APL is also exquisitely sensitive to arsenic trioxide and both RA and arsenic directly target the PML/RARa fusion protein,identifying the first example of differentiation therapy and oncogene-targeted therapies.This article mainly reviews how APL occurs and the progress of RA curing for APL.