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Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure

机译：急性幼幼儿细胞白血病：癌蛋白靶向治疗的范式

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Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions. Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.
机译：最近的临床试验表明，绝大多数急性早幼粒细胞白血病（APL）患者可以通过两种靶向疗法的组合最终治愈：维甲酸（RA）和砷。小鼠模型对相关机制提供了意想不到的见解。RA和/或砷引发PML/RARA降解后PML核小体的恢复至关重要，而RA触发的转录激活对于APL根除是必不可少的。在治疗耐药患者中检测到PML/RARA的砷结合位点突变，但也检测到PML，表明PML在APL治疗中的关键作用。PML的核体是可药物化的，可以在其他条件下使用。最近的临床试验表明，绝大多数急性早幼粒细胞白血病（APL）患者可以通过两种靶向疗法的组合最终治愈：维甲酸（RA）和砷。小鼠模型对相关机制提供了意想不到的见解。RA和/或砷引发PML/RARA降解后PML核小体的恢复至关重要，而RA触发的转录激活对于APL根除是必不可少的。在治疗耐药患者中检测到PML/RARA的砷结合位点突变，但也检测到PML，表明PML在APL治疗中的关键作用。PML的核体是可药物化的，可以在其他条件下使用。

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