{"doi":"10.1158/2159-8290.cd-22-0561","title":"An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas","abstract":"A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extranodal dissemination, which is associated with inferior clinical outcomes. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate with minimal T-cell costimulation. Additionally, Myd88L252P skewed B cells toward memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B cells of their competitive fitness. By identifying a phenotypically defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients. SIGNIFICANCE: Extranodal lymphomas feature a very poor prognosis. The identification of phenotypically distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diagnosis, patient stratification, and prophylactic interventions. Conceptually, we found that extranodal lymphomas and autoimmune disorders harness overlapping pathogenic trajectories, suggesting these B-cell disorders develop and evolve within a spectrum. See related commentary by Leveille et al. (Blood Cancer Discov 2023;4:8-11). This article is highlighted in the In This Issue feature, p. 1.","journal":"Cancer Discovery","year":2022,"id":255810,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255168,"name":"Martín A. Rivas","orcid":"0000-0002-9603-6897","position":1,"is_corresponding":false},{"id":470969,"name":"Benedikt W. Pelzer","orcid":"0000-0002-1892-3650","position":2,"is_corresponding":false},{"id":470963,"name":"Ruth Flümann","orcid":"0000-0002-7147-7557","position":3,"is_corresponding":false},{"id":904139,"name":"Julia Hansen","orcid":"0000-0001-7828-1269","position":4,"is_corresponding":false},{"id":470303,"name":"Ioannis Karagiannidis","orcid":"0000-0001-5850-957X","position":5,"is_corresponding":false},{"id":903158,"name":"Min Xia","orcid":"0000-0002-1093-5008","position":6,"is_corresponding":false},{"id":361880,"name":"Dylan McNally","orcid":"0000-0001-7831-0349","position":7,"is_corresponding":false},{"id":904140,"name":"Yusuke Isshiki","orcid":"0000-0003-0789-6789","position":8,"is_corresponding":false},{"id":246052,"name":"Andrew Lytle","orcid":"0000-0002-9979-3690","position":9,"is_corresponding":false},{"id":237405,"name":"Matt Teater","orcid":"0000-0001-9415-1659","position":10,"is_corresponding":false},{"id":237408,"name":"Christopher R. Chin","orcid":"0000-0002-2140-3197","position":11,"is_corresponding":false},{"id":227777,"name":"Cem Meydan","orcid":"0000-0002-0663-6216","position":12,"is_corresponding":false},{"id":470983,"name":"Gero Knittel","orcid":"0000-0001-8395-3701","position":13,"is_corresponding":false},{"id":420513,"name":"Edd Ricker","orcid":"0000-0001-8779-1105","position":14,"is_corresponding":false},{"id":36370,"name":"Christopher E. Mason","orcid":"0000-0002-1850-1642","position":15,"is_corresponding":false},{"id":852565,"name":"Xiaofei Ye","orcid":"0000-0002-7678-1152","position":16,"is_corresponding":false},{"id":14420,"name":"Qiang Pan‐Hammarström","orcid":"0000-0003-1990-8804","position":17,"is_corresponding":false},{"id":255172,"name":"Christian Steidl","orcid":"0000-0001-9842-9750","position":18,"is_corresponding":false},{"id":106831,"name":"David W. Scott","orcid":"0000-0002-0435-5947","position":19,"is_corresponding":false},{"id":332516,"name":"Hans Christian Reinhardt","orcid":"0000-0001-5706-9349","position":20,"is_corresponding":false},{"id":420518,"name":"Alessandra B. Pernis","orcid":"0000-0001-8259-1446","position":21,"is_corresponding":false},{"id":237414,"name":"Wendy Béguelin","orcid":"0000-0002-4894-9229","position":22,"is_corresponding":false},{"id":237422,"name":"Ari Melnick","orcid":"0000-0002-8074-2287","position":23,"is_corresponding":false},{"id":255167,"name":"Leandro Venturutti","orcid":"0000-0002-7264-8370","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-19T00:25:17.224217Z","pmid":"36264161","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":[]}