Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins
Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins
复制标题
高温选择性地破坏致癌融合蛋白的稳定性
DOI：
10.1158/2643-3230.bcd-20-0188
复制
发表时间：
2021-07-01
影响因子：
11.2
通讯作者：
Naranmandura, Hua
中科院分区：
文献类型：
--
作者：
Maimaitiyiming, Yasen;Wang, Qian Qian;Naranmandura, Hua
PML/RAR α 融合蛋白是急性早幼粒细胞白血病 (APL) 的致癌驱动因素。尽管大多数 APL 病例可通过 PML/RAR α 靶向治疗治愈，但由于耐药突变，可能会出现复发和耐药。在此，我们报告热应激会破坏 PML/RAR α 蛋白的稳定性，包括临床鉴定的耐药突变体。 AML1/ETO 和 TEL/AML1 肿瘤融合表现出相似的热休克敏感性。从机制上讲，温和的高温会刺激 PML/RAR α 与核受体辅阻遏物复合物的聚集，从而通过 SIAH2 E3 连接酶导致泛素介导的降解。热疗和砷疗法通过不同的机制破坏 PML/RAR α 的稳定性，并且在原始患者样本和体内（包括三例难治性 APL 病例）中具有协同作用。总的来说，我们的结果表明，通过利用 PML/RAR α 的生物物理脆弱性，热疗法可以改善耐药或难治性 APL 的预后。这些发现为通过热疗靶向治疗融合癌蛋白相关癌症提供了范例。意义：热疗会破坏肿瘤融合蛋白（包括 PML/RAR α）的稳定性，并与标准砷疗法在复发性和难治性 APL 中发挥协同作用。结果表明，热休克敏感性可能是肿瘤融合驱动的癌症的一个易于靶向的脆弱性。
The PML/RAR alpha fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RAR alpha-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RAR alpha protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RAR alpha in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RAR alpha via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RAR alpha, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia.SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RAR alpha and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.