Li Wei, Wang Ruirui, Wang Junhao, Chai Dafei, Xie Xiaohui, Young Ken H, Cao Ya, Li Yong, Yu Xinfang
Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.
Blood. 2025 Mar 6;145(10):1047-1060. doi: 10.1182/blood.2024026781.
Myeloid differentiation primary response protein 88 (MYD88) is a key adaptor molecule in the signaling pathways of toll-like receptor and interleukin-1 receptor. A somatic mutation resulting in a leucine-to-proline change at position 265 of the MYD88 protein (MYD88 L265P) is one of the most prevalent oncogenic mutations found in patients with hematological malignancies. In this study, we used high-throughput screening to identify lasalocid A as a potent small molecule that selectively inhibited the viability of lymphoma cells expressing MYD88 L265P and the associated activation of NF-κB. Further investigations using CRISPR-CRISPR-associated protein 9 genetic screening, proteomics, and biochemical assays revealed that lasalocid A directly binds to the MYD88 L265P protein, enhancing its interaction with the ubiquitin ligase RNF5. This interaction promotes MYD88 degradation through the ubiquitin-dependent proteasomal pathway, specifically in lymphomas with the MYD88 L265P mutation. Lasalocid A exhibited strong antitumor efficacy in xenograft mouse models, induced disease remission in ibrutinib-resistant lymphomas, and showed synergistic activity with the B-cell lymphoma 2 inhibitor venetoclax. This study highlights the potential of inducing MYD88 L265P degradation using small molecules, offering promising strategies for treating lymphomas that harbor the MYD88 L265P mutation.
髓样分化初级反应蛋白88（MYD88）是Toll样受体和白细胞介素-1受体信号通路中的关键衔接分子。导致MYD88蛋白第265位亮氨酸变为脯氨酸的体细胞突变（MYD88 L265P）是血液系统恶性肿瘤患者中最常见的致癌突变之一。在本研究中，我们使用高通量筛选鉴定出拉沙洛西A是一种有效的小分子，可选择性抑制表达MYD88 L265P的淋巴瘤细胞的活力以及相关的核因子κB激活。使用CRISPR- CRISPR相关蛋白9基因筛选、蛋白质组学和生化分析的进一步研究表明，拉沙洛西A直接与MYD88 L265P蛋白结合，增强其与泛素连接酶RNF5的相互作用。这种相互作用通过泛素依赖性蛋白酶体途径促进MYD88降解，特别是在具有MYD88 L265P突变的淋巴瘤中。拉沙洛西A在异种移植小鼠模型中表现出强大的抗肿瘤功效，在依鲁替尼耐药的淋巴瘤中诱导疾病缓解，并与B细胞淋巴瘤2抑制剂维奈克拉显示出协同活性。本研究突出了使用小分子诱导MYD88 L265P降解的潜力，为治疗携带MYD88 L265P突变的淋巴瘤提供了有前景的策略。
