Translocations of the RARa gene in acute promyelocytic leukemia
Translocations of the RARa gene in acute promyelocytic leukemia
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发表时间：
2001
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通讯作者：
A. Zelent;F. Guidez;A. Melnick;S. Waxman;J. Licht
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作者：
A. Zelent;F. Guidez;A. Melnick;S. Waxman;J. Licht
急性早幼粒细胞白血病（APL）作为一种独特的临床实体已经被认识了40多年。虽然在造血系统恶性肿瘤中相对罕见（约占AML病例的10%），但这种疾病已引起了特别好的关注，成为第一种全反式维甲酸（ATRA）（维生素A的生理活性衍生物）能够诱导完全缓解（CR）的人类癌症。全反式维甲酸诱导的缓解与常规化疗中的快速细胞死亡无关，而是与“正常”粒细胞分化途径的恢复有关。有了这个非凡的医学成功故事，APL一夜之间成为癌症透析治疗的典范。几年后，APL的兴奋进一步增强，因为发现这种疾病的细胞遗传学标记，t（15：17）相互染色体易位，涉及维甲酸受体α（RARa）基因和以前未知的名为早幼粒细胞白血病（PML）的基因座之间的融合。这种基因重排的结果是PML-RAR α嵌合癌蛋白的表达，其负责细胞转化以及在APL中观察到的ATRA反应。自从这一发现以来，在罕见的APL病例中已经报道了许多RAR α的不同易位伴侣基因，这强烈表明RAR α的破坏是其发病机制的基础。本文综述了迄今为止文献中所描述的RAR α基因的各种重排、不同RAR α伴侣基因座编码的蛋白质的功能以及这些蛋白质可能对APL分子发病机制的影响。Oncogene（2001）20，7186 - 7203.
Acute promyelocytic leukemia (APL) has been recognized as a distinct clinical entity for over 40 years. Although relatively rare among hematopoietic malignancies (approximately 10% of AML cases), this disease has attracted a particularly good share of attention by becoming the first human cancer in which all-transretinoic acid (ATRA), a physiologically active derivative of vitamin A, was able to induce complete remission (CR). ATRA induced remission is not associated with rapid cell death, as in the case of conventional chemotherapy, but with a restoration of the ‘normal’ granulocytic diAerentiation pathway. With this remarkable medical success story APL has overnight become a paradigm for the diAerentiation therapy of cancer. A few years later, excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease, the t(15:17) reciprocal chromosomal translocation, involves a fusion between the retinoic acid receptor alpha (RARa) gene and a previously unknown locus named promyelocytic leukemia (PML). Consequence of this gene rearrangement is expression of the PML‐RARa chimeric oncoprotein, which is responsible for the cellular transformation as well as ATRA response that is observed in APL. Since this initial discovery, a number of diAerent translocation partner genes of RARa have been reported in rarer cases of APL, strongly suggesting that disruption of RARa underlies its pathogenesis. This article reviews various rearrangements of the RARa gene that have so far been described in literature, functions of the proteins encoded by the diAerent RARa partner loci, and implications that these may have for the molecular pathogenesis of APL. Oncogene (2001) 20, 7186‐7203.