致癌融合蛋白早幼粒细胞白血病/视黄酸受体α (PML/RARα) 对于急性早幼粒细胞白血病 (APL) 至关重要。 PML/RARα 通过阻断分化和增加白血病细胞的自我更新来启动 APL。标准临床疗法全反式视黄酸（ATRA）和三氧化二砷（ATO）可诱导 PML/RARα 蛋白水解，显着改善 APL 患者的预后。然而，ATRA 和 ATO 耐药突变的出现给 APL 患者的治疗带来了挑战。探索调节 PML/RARα 致癌活性的途径可能有助于开发新的 APL 治疗策略，特别是耐药 APL。在此，我们首次证明 PML/RARα 的棕榈酰化是其致癌活性的关键决定因素。发现 PML/RARα 棕榈酰化主要由棕榈酰转移酶 ZDHHC3 催化。从机制上讲，ZDHHC3 介导的棕榈酰化调节 PML/RARα 的致癌转录活性和 APL 发病机制。 ZDHHC3的敲低或过表达分别对增殖和分化相关基因的表达产生影响。一致地，ZDHHC3的缺失或抑制可以显着阻止APL的恶性进展，特别是耐药APL，而ZDHHC3的过表达似乎对APL的恶性进展具有促进作用。因此，我们的研究不仅揭示了棕榈酰化作为一种​​调节 PML/RARα 致癌活性的新型调控机制，而且还确定了 ZDHHC3 作为 APL（包括耐药 APL）的潜在治疗靶点。© 2024。作者，拥有独家许可中国科学院上海药物研究所、中国药理学会。

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.