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.

中文翻译：

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急性早幼粒细胞白血病的分子发病机制：对疾病的临床管理的影响。

急性早幼粒细胞白血病（APL）的特征是17q21的染色体重排，导致编码视黄酸受体α（RARalpha）的基因与许多替代伴侣基因（X）融合，其中最常见的是PML（> 95％ ），PLZF（0.8％）和NPM（0.5％）。在过去的几年中，已经确定，X-RARalpha融合蛋白通过募集共阻遏物和组蛋白脱乙酰基酶（HDAC）复合物阻遏与髓样分化有关的基因，在APL的发病机理中起关键作用。矛盾的是，X-RARalpha融合蛋白具有介导其配体（全反式维甲酸（ATRA））的药理剂量的髓系分化的潜力，这取决于HDAC /共阻遏物复合物的解离。砷化合物也已被证明是有前途的治疗剂，可导致APL母细胞的分化和凋亡。现在很明显，RARalpha融合伴侣的性质是对ATRA和砷反应的关键决定因素，强调了对疑似APL患者进行细胞遗传学和分子表征的重要性，以确定最合适的治疗方法。涉及ATRA与基于蒽环类药物的化学疗法相结合的标准方案可治愈约70％的PML-RARalpha相关APL患者。可以通过最少的残留疾病监测来识别高复发风险的患者。未来研究面临的挑战是通过减少诱导死亡（尤其是出血引起的死亡）来提高完全缓解率，识别可从其他治疗中受益的高复发风险患者，以及可降低治疗强度的有利风险人群，从而降低治疗毒性和继发性白血病/骨髓增生异常的风险。随着ATRA和砷的出现，APL已经提供了成功的分子靶向疗法的第一个例子；希望随着对疾病发病机理的进一步了解，未来十年将使这些患者的前景得到进一步改善。APL已经提供了成功的分子靶向治疗的第一个例子；希望随着对疾病发病机理的进一步了解，未来十年将使这些患者的前景得到进一步改善。APL已经提供了成功的分子靶向治疗的第一个例子；希望对疾病的发病机理有进一步的了解，未来十年将使这些患者的前景得到进一步改善。