Mistry Anita R, Pedersen Eva W, Solomon Ellen, Grimwade David
Division of Medical and Molecular Genetics, Guy's, King's and St Thomas' School of Medicine, London, UK.
Blood Rev. 2003 Jun;17(2):71-97. doi: 10.1016/s0268-960x(02)00075-9.
Acute promyelocytic leukaemia (APL) is characterised by chromosomal rearrangements of 17q21, leading to fusion of the gene encoding retinoic acid receptor alpha (RARalpha) to a number of alternative partner genes (X), the most frequent of which are PML (>95%), PLZF (0.8%) and NPM (0.5%). Over the last few years, it has been established that the X-RARalpha fusion proteins play a key role in the pathogenesis of APL through recruitment of co-repressors and the histone deacetylase (HDAC)-complex to repress genes implicated in myeloid differentiation. Paradoxically, the X-RARalpha fusion protein has the potential to mediate myeloid differentiation at pharmacological doses of its ligand (all trans-retinoic acid (ATRA)), which is dependent on the dissociation of the HDAC/co-repressor complex. Arsenic compounds have also been shown to be promising therapeutic agents, leading to differentiation and apoptosis of APL blasts. It is now apparent that the nature of the RARalpha-fusion partner is a critical determinant of response to ATRA and arsenic, underlining the importance of cytogenetic and molecular characterisation of patients with suspected APL to determine the most appropriate treatment approach. Standard protocols involving ATRA combined with anthracycline-based chemotherapy, lead to cure of approximately 70% patients with PML-RARalpha-associated APL. Patients at high risk of relapse can be identified by minimal residual disease monitoring. The challenge for future studies is to improve complete remission rates through reduction of induction deaths, particularly due to haemorrhage, identification of patients at high risk of relapse who would benefit from additional therapy, and identification of a favourable-risk group, for which treatment intensity could be reduced, thereby reducing risks of treatment toxicity and development of secondary leukaemia/myelodysplasia. With the advent of ATRA and arsenic, APL has already provided the first example of successful molecularly targeted therapy; it is hoped that with further understanding of the pathogenesis of the disease, the next decade will yield further improvements in the outlook for these patients.
急性早幼粒细胞白血病（APL）的特征是17q21染色体重排，导致编码维甲酸受体α（RARα）的基因与多个不同的伙伴基因（X）融合，其中最常见的是PML（>95%）、PLZF（0.8%）和NPM（0.5%）。在过去几年中，已证实X-RARα融合蛋白通过募集共抑制因子和组蛋白去乙酰化酶（HDAC）复合物来抑制与髓系分化相关的基因，从而在APL的发病机制中起关键作用。矛盾的是，X-RARα融合蛋白在其配体（全反式维甲酸（ATRA））的药理剂量下具有介导髓系分化的潜力，这取决于HDAC/共抑制因子复合物的解离。砷化合物也已被证明是有前景的治疗药物，可导致APL原始细胞的分化和凋亡。现在很明显，RARα融合伙伴的性质是对ATRA和砷反应的关键决定因素，这突出了对疑似APL患者进行细胞遗传学和分子特征分析以确定最合适治疗方法的重要性。涉及ATRA联合蒽环类化疗的标准方案可使约70%的PML-RARα相关APL患者治愈。通过微小残留病监测可识别出复发高危患者。未来研究的挑战在于通过减少诱导期死亡（特别是因出血导致的死亡）来提高完全缓解率，识别出可从额外治疗中获益的复发高危患者，以及识别出可降低治疗强度从而降低治疗毒性和继发性白血病/骨髓增生异常综合征发生风险的低危组。随着ATRA和砷的出现，APL已成为成功的分子靶向治疗的首个范例；希望随着对该疾病发病机制的进一步了解，未来十年这些患者的预后将得到进一步改善。
