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恶性细胞的表型是否可能逆转?长期以来,科学家们一直在研究一种肿瘤治疗的新途径,即通过启动恶性细胞的成熟和程序化死亡达到分化治疗。急性早幼粒细胞白血病(APL)是应用分化诱导剂——全反式维甲酸(ATRA)治疗成功的第一个人类肿瘤。该病的另一特点是有特异染色体易位t(15;17)。在研究APL细胞对ATRA的应答机理中,我们和其他作者阐明了t(15;17)的分子生物学,发现它使维甲酸受体α基因(RARA)与15号染色体上的一个位点PML发生融合。功能研究显示PML-RARA的行为不同于野生型RARA。这一白血病标志的直接临床应用是发展了一种针对PML-RARA融合转录本的逆转录酶/PCR分析。最近,我们又发现了一种新的变异型易位t(11;17),该易位使RARA与11q23上一个被称之为早幼粒白血病锌指蛋白(PLZF)的基因发生融合。PLZF编码一个含有9个锌指的蛋白,可能是一个转录因子。在t(15;17)和t(11;17)两种易位中,RARA是共同靶子的事实提示RARA在APL发病原理中起着重要作用,应用转染试验,我们显示PLZF-RARA和PML-RARA一样,对野生型RARA具有“显性负”作用。近来在白种人APL中发现了具有t(11;17)的病例。虽然伴t(15;17)的APL患者对ATRA均有良好疗效,伴t(11;17)的患者则反应不佳,提示可能是APL中的一种新的临床综合征。对PML-RARA和PLZF-RA
Whether the phenotype of malignant cells may be reversed? For a long time, scientists have been studying a new way of cancer treatment, that is, to achieve differentiation treatment by initiating the maturation of malignant cells and programmed death. Acute promyelocytic leukemia (APL) is the first human tumor successfully treated with all-trans retinoic acid (ATRA) using a differentiation inducer. Another feature of the disease is the specific chromosomal translocation t (15; 17). In studying the mechanism of response of APL cells to ATRA, we and other authors have elucidated the molecular biology of t(15;17) and found that it makes the retinoid receptor alpha gene (RARA) and a locus on chromosome 15 PML. Fusion occurs. Functional studies show that PML-RARA behaves differently than wild-type RARA. A direct clinical application of this leukemia marker is the development of a reverse transcriptase/PCR assay for PML-RARA fusion transcripts. Recently, we have also discovered a new variant translocation t(11;17) that allows RARA to fuse with a gene called 11PL23 that is known as promyelocytic zinc finger protein (PLZF). PLZF encodes a protein containing 9 zinc fingers, which may be a transcription factor. The fact that RARA is a common target in both t(15;17) and t(11;17) translocation suggests that RARA plays an important role in the pathogenesis of APL. Using transfection experiments, we show that PLZF-RARA and PML Like RARA, it has a “dominant negative” effect on wild-type RARA. Cases with t(11;17) have recently been found in Caucasian APL. Although patients with APL with t(15;17) have good results for ATRA, patients with t(11;17) have poor response, suggesting that it may be a new clinical syndrome in APL. For PML-RARA and PLZF-RA