文章：

急性早幼粒细胞白血病：治疗机制的新见解

Acute promyelocytic leukaemia: novel insights into the mechanisms of cure

原文发布日期：2010-10-22

DOI: 10.1038/nrc2943

类型: Review Article

开放获取: 否

要点：

1. Promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα) is a gain-of-function protein that represses RARα and non-RARα target genes and disrupts PML nuclear bodies. This results in immortal proliferation and the inhibition of terminal differentiation.
2. Various clinical regimens combining retinoic acid (RA), arsenic trioxide and anthracyclines now definitively cure up to 90% of patients with acute promyelocytic leukaemia (APL).
3. RA induces APL differentiation and transient remissions. Arsenic trioxide triggers both apoptosis and differentiation and, as a single agent, allows many APL cures. As initially shown in mouse models, their combination definitively cures most patients.
4. Mechanistically, therapy-induced transcriptional activation (or derepression) is responsible for APL cell differentiation, and PML–RARα degradation by RA or arsenic trioxide results in APL eradication.
5. Arsenic trioxide targets PML through oxidation-triggered disulphide bond formation and direct binding. This results in PML and PML–RARα sumoylation, ubiquitylation and proteasome-mediated degradation.
6. Therapy-triggered oncoprotein degradation could be a generally applicable strategy to treat malignancies driven by fusion proteins or overactivation of transcription factors.

要点翻译：

1. 早幼粒细胞白血病（PML）-视黄酸受体α（RARα）是一种功能获得性蛋白，可抑制RARα和非RARα靶基因，并破坏PML核体。这导致细胞永生化增殖并抑制终末分化。
2. 目前联合使用视黄酸（RA）、三氧化二砷和蒽环类药物的多种临床方案，已能明确治愈高达90%的急性早幼粒细胞白血病（APL）患者。
3. RA可诱导APL细胞分化并实现短暂缓解。三氧化二砷能同时触发细胞凋亡与分化，作为单一药物即可治愈多数APL患者。如小鼠模型初步所示，两者联合治疗可彻底治愈大多数患者。
4. 从机制上看，治疗诱导的转录激活（或去抑制）是APL细胞分化的关键因素，而RA或三氧化二砷介导的PML–RARα降解则实现了APL的根除。
5. 三氧化二砷通过氧化触发二硫键形成和直接结合靶向PML，导致PML和PML–RARα发生SUMO化、泛素化及蛋白酶体介导的降解。
6. 治疗触发的癌蛋白降解策略，或可普遍适用于由融合蛋白或转录因子过度激活驱动的恶性肿瘤治疗。

英文摘要：

The fusion oncogene, promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML–RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

摘要翻译： 

融合癌基因早幼粒细胞白血病（PML）-维甲酸受体α（RARA）通过阻断分化并增加白血病祖细胞的自我更新，启动急性早幼粒细胞白血病（APL）。目前的标准治疗是维甲酸（RA）联合化疗，但三氧化二砷也能治愈许多APL患者，且RA加三氧化二砷的联合方案可治愈大多数患者。本综述讨论了最新证据，揭示出RA和三氧化二砷通过靶向降解PML–RARα来治愈该白血病的惊人新机制。药物触发癌蛋白降解或许可成为适用于多种癌症的治疗策略。

原文链接：

Acute promyelocytic leukaemia: novel insights into the mechanisms of cure