维甲酸诱导早幼粒白血病细胞分化的分子机制研究

STUDY ON THE MOLECULAR MECHANISM OF THE DIFFERENTIATION OF ACUTE PROMYELOCYTIC LEUKEMIA CELLS INDUCED WITH RETINOIC ACID

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。

Is the phenotype of malignant cells reversible? For a long time, scientists have been working on a new approach of cancer treatment,the differentiation therapy, by triggering malignant cells' maturation and programmed cell death. Acute promyelocytic leukemia (APL) has been the first example of human cancer which can be effectively treated with a differentiation inducer-all-trans retinoic acid (ATRA). APL is also characterized by the specific chromosomal translocation t (15; 17 ). In studying the mechanisms responsible for the response of APL cells to ATRA, we and others have been able to characterize the molecular biology of t (15; 17 ) which fuses the retinoic acid receptor aaaaaaaaaaaaaaa(RARA) gene with a chromosome 15q locus, PML. Functional studies demonstrate that PML- RARA behaves differently from the wild-type RARA. A direct clinical application of this leukemia marker has been the development of the retrotranscriptase/PCR analysis of PML-RARA fusion transcripts which allows the rapid diagnosis of APL. Recently, we have identified a new, variant translocation t (11; 17) and showed that RARA is fused with a new gene on chromosome 11q23. This gene named PLZF for promyelocytic leukemia zinc finger encodes a protein containing 9 zinc-finger motifs and is probably a transcription factor. The fact that RARA is the common target in both t (15; 17 ) and t ( 11; 17) suggests its crucial role in the pathogenesis of APL. Using transient transfection systems in COS cells as well as in human myeloid cell lines, we show that the PLZF-RARA, like PML-RARA, has a 'dominant negative' effect on the wild-type RARA. Recently, similar cases have also been found in Caucasian APL. It has been shown that although APL patients with t(15;17) have good response to ATRA, those cases bearing t (11; 17 ) respond poorly and could represent a special clinical syndrome within APL. A comparative study on PML-RARA and PLZF- RARA will certainly give new insight for understanding the mechanism underlying the ATRA-induced cell differentiation.