Department of Oncology, Istituto Superiore di Sanità, Rome, Italy.
Adv Exp Med Biol. 2024;1459:321-339. doi: 10.1007/978-3-031-62731-6_14.
The transformation of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML), with long-term survival exceeding 90%, has represented one of the most exciting successes in hematology and in oncology. APL is a paradigm for oncoprotein-targeted cure.APL is caused by a 15/17 chromosomal translocation which generates the PML-RARA fusion protein and can be cured by the chemotherapy-free approach based on the combination of two therapies targeting PML-RARA: retinoic acid (RA) and arsenic. PML-RARA is the key driver of APL and acts by deregulating transcriptional control, particularly RAR targets involved in self-renewal or myeloid differentiation, also disrupting PML nuclear bodies. PML-RARA mainly acts as a modulator of the expression of specific target genes: genes whose regulatory elements recruit PML-RARA are not uniformly repressed but also may be upregulated or remain unchanged. RA and arsenic trioxide directly target PML-RARA-mediated transcriptional deregulation and protein stability, removing the differentiation block at promyelocytic stage and inducing clinical remission of APL patients.
急性早幼粒细胞白血病（APL）从最致命的急性髓系白血病（AML）亚型转变为最可治愈的亚型，长期生存率超过 90%，这是血液学和肿瘤学领域最令人兴奋的成功之一。APL 是一种针对癌蛋白的靶向治疗的范例。APL 是由 15/17 染色体易位引起的，该易位会产生 PML-RARA 融合蛋白，并可通过基于两种针对 PML-RARA 的治疗方法联合的无化疗方法治愈：维甲酸（RA）和砷剂。PML-RARA 是 APL 的关键驱动因素，通过解除转录控制来发挥作用，特别是涉及自我更新或髓样分化的 RAR 靶标，也破坏了 PML 核体。PML-RARA 主要作为特定靶基因表达的调节剂：其调节元件募集 PML-RARA 的基因不是均匀被抑制，也可能被上调或保持不变。RA 和三氧化二砷直接靶向 PML-RARA 介导的转录失调和蛋白质稳定性，消除早幼粒细胞阶段的分化障碍，并诱导 APL 患者的临床缓解。
