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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-\u03baB. Further investigations using CRISPR-CRISPR\u2013associated 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024026781","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T16:11:57Z","timestamp":1732291917000},"page":"1047-1060","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":5,"title":["Lasalocid A selectively induces the degradation of MYD88 in lymphomas harboring the MYD88 L265P mutation"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-6494","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"first","affiliation":[{"name":"1Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China"},{"name":"2Department of Medicine, Dan L Duncan Comprehensive 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