{"doi":"10.1101/2023.03.13.532151","title":"Dynamic phosphatase-recruitment controls B-cell selection and oncogenic signaling","abstract":"Initiation of B-cell receptor (BCR) 1 signaling, and subsequent antigen-encounter in germinal centers 2,3 represent milestones of B-lymphocyte development that are both marked by sharp increases of CD25 surface-expression. Oncogenic signaling in B-cell leukemia (B-ALL) 4 and lymphoma 5 also induced CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells 6–9 , the significance of its expression on B-cells was unclear. Our experiments based on genetic mouse models and engineered patient-derived xenografts revealed that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells assembled an inhibitory complex including PKCδ and SHIP1 and SHP1 phosphatases for feedback control of BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKCδ 10 – 12 , SHIP1 13,14 and SHP1 14, 15,16 , conditional CD25-deletion decimated early B-cell subsets but expanded mature B-cell populations and induced autoimmunity. In B-cell malignancies arising from early (B-ALL) and late (lymphoma) stages of B-cell development, CD25-loss induced cell death in the former and accelerated proliferation in the latter. Clinical outcome annotations mirrored opposite effects of CD25-deletion: high CD25 expression levels predicted poor clinical outcomes for patients with B-ALL, in contrast to favorable outcomes for lymphoma-patients. Biochemical and interactome studies revealed a critical role of CD25 in BCR-feedback regulation: BCR-signaling induced PKCδ-mediated phosphorylation of CD25 on its cytoplasmic tail (S 268 ). Genetic rescue experiments identified CD25-S 268 tail-phosphorylation as central structural requirement to recruit SHIP1 and SHP1 phosphatases to curb BCR-signaling. A single point mutation CD25 S268A abolished recruitment and activation of SHIP1 and SHP1 to limit duration and strength of BCR-signaling. Loss of phosphatase-function, autonomous BCR-signaling and Ca 2+ -oscillations induced anergy and negative selection during early B-cell development, as opposed to excessive proliferation and autoantibody production in mature B-cells. These findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to control oncogenic signaling in B-cell malignancies and negative selection to prevent autoimmune disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393048,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":272473,"name":"Mark E. Robinson","orcid":"0000-0003-2363-6047","position":1,"is_corresponding":false},{"id":333144,"name":"Ruifeng Sun","orcid":null,"position":2,"is_corresponding":false},{"id":272483,"name":"Kohei Kume","orcid":"0000-0003-2856-5970","position":3,"is_corresponding":false},{"id":272474,"name":"Ning Ma","orcid":"0000-0003-4653-7797","position":4,"is_corresponding":false},{"id":272481,"name":"Kadriye Nehir Cosgun","orcid":"0000-0003-4181-744X","position":5,"is_corresponding":false},{"id":273270,"name":"Lai N. Chan","orcid":null,"position":6,"is_corresponding":false},{"id":301065,"name":"Etienne Léveillé","orcid":"0000-0001-5269-9544","position":7,"is_corresponding":false},{"id":272482,"name":"Huimin Geng","orcid":"0000-0001-5339-5446","position":8,"is_corresponding":false},{"id":805859,"name":"Vivasvan S. Vykunta","orcid":"0000-0002-5409-8635","position":9,"is_corresponding":false},{"id":235385,"name":"Brian R. Shy","orcid":"0000-0001-9569-3708","position":10,"is_corresponding":false},{"id":30775,"name":"Alexander Marson","orcid":"0000-0002-2734-5776","position":11,"is_corresponding":false},{"id":270683,"name":"Samuel G. Katz","orcid":"0000-0003-1744-8568","position":12,"is_corresponding":false},{"id":106277,"name":"Jianjun Chen","orcid":"0000-0003-3749-2902","position":13,"is_corresponding":false},{"id":241452,"name":"Elisabeth Paietta","orcid":"0000-0002-0561-5544","position":14,"is_corresponding":false},{"id":395328,"name":"Eric Meffre","orcid":"0000-0003-4326-0171","position":15,"is_corresponding":false},{"id":272488,"name":"Nagarajan Vaidehi","orcid":"0000-0001-8100-8132","position":16,"is_corresponding":false},{"id":108573,"name":"Markus Müschen","orcid":"0000-0002-6064-8613","position":17,"is_corresponding":false},{"id":272472,"name":"Jae Woong Lee","orcid":"0000-0001-7952-5544","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:19:01.355412Z","pmid":"36993276","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":[]}