{"doi":"10.1182/blood.2020004918","title":"MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis","abstract":"Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT, which is critical to innate immunity.","journal":"Blood","year":2020,"id":63842,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":263249,"name":"Wei Li","orcid":"0000-0001-9931-5990","position":1,"is_corresponding":false},{"id":337594,"name":"Qipan Deng","orcid":"0000-0002-3803-1676","position":2,"is_corresponding":false},{"id":337595,"name":"Haidan Liu","orcid":"0000-0002-6062-0813","position":3,"is_corresponding":false},{"id":337596,"name":"Xu Wang","orcid":"0000-0001-8428-9339","position":4,"is_corresponding":false},{"id":337597,"name":"Hui Hu","orcid":"0000-0002-9208-1041","position":5,"is_corresponding":false},{"id":134903,"name":"Ya Cao","orcid":"0000-0002-3558-3336","position":6,"is_corresponding":false},{"id":288532,"name":"Zijun Y. Xu‐Monette","orcid":"0000-0002-7615-3949","position":7,"is_corresponding":false},{"id":288533,"name":"Ling Li","orcid":"0009-0000-7691-7315","position":8,"is_corresponding":false},{"id":288534,"name":"Mingzhi Zhang","orcid":"0000-0003-3581-551X","position":9,"is_corresponding":false},{"id":337598,"name":"Zhongxin Lu","orcid":"0000-0002-3365-0881","position":10,"is_corresponding":false},{"id":288535,"name":"Ken H. Young","orcid":"0000-0002-5755-8932","position":11,"is_corresponding":false},{"id":288537,"name":"Yong Li","orcid":"0000-0001-8838-1714","position":12,"is_corresponding":false},{"id":288530,"name":"Xinfang Yu","orcid":"0000-0003-3738-7133","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T21:11:24.000992Z","pmid":"33025009","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}