Lutz P G, Moog-Lutz C, Cayre Y E
Unité INSERM U417, Hôpital Saint Antoine, Paris, France.
Leukemia. 2002 Oct;16(10):1933-9. doi: 10.1038/sj.leu.2402728.
Although transcription factors are still the main focus to understanding leukemogenesis, recent results strongly suggest that alteration of a receptor and/or subsequent signaling plays a critical and co-operative role in the pathogenesis of acute myeloid leukemia (AML). The t(15;17) translocation, found in 95% of APL, encodes a PML-RARalpha fusion protein. A main model proposed for acute promyelocytic leukemia (APL) is that PML-RARalpha exerts its oncogenic effects by repressing retinoic acid-inducible genes critical to myeloid differentiation. Dysregulation of these genes may result in abnormal signaling, thereby freeing pre-leukemic cells from controls which normally induce the onset of differentiation. It is also likely that treatment of APL cells by retinoic acid induces de novo up-regulation of the same genes which are dominantly repressed by PML-RARalpha and whose expression is required for reactivation of the differentiation program. Identification of such genes together with the signaling pathways interrupted at the early stages of leukemia transformation and reactivated during retinoic acid-induced differentiation in APL cells will contribute to the development of new molecular targets for treatment of leukemia.
尽管转录因子仍是理解白血病发生的主要焦点，但最近的研究结果强烈表明，受体的改变和/或随后的信号传导在急性髓系白血病（AML）的发病机制中起着关键的协同作用。在95%的急性早幼粒细胞白血病（APL）中发现的t(15;17)易位编码一种PML-RARα融合蛋白。针对急性早幼粒细胞白血病（APL）提出的一个主要模型是，PML-RARα通过抑制对髓系分化至关重要的视黄酸诱导基因发挥其致癌作用。这些基因的失调可能导致异常信号传导，从而使白血病前期细胞摆脱正常诱导分化开始的控制。同样有可能的是，用视黄酸处理APL细胞会诱导那些被PML-RARα主要抑制且其表达对于重新激活分化程序是必需的相同基因的从头上调。鉴定这些基因以及在白血病转化早期被中断并在APL细胞视黄酸诱导分化过程中重新激活的信号通路，将有助于开发治疗白血病的新分子靶点。
