{"doi":"10.26508/lsa.202503222","title":"STAT5B leukemic mutations, altering SH2 tyrosine 665, have opposing impacts on immune gene programs","abstract":"STAT5B is a vital transcription factor for lymphocytes. Here, the function of two STAT5B mutations from human T-cell leukemias: one substituting tyrosine 665 with phenylalanine (STAT5B Y665F ) and the other with histidine (STAT5B Y665H ), was interrogated. In silico modeling predicted divergent energetic effects on homodimerization with a range of pathogenicity. In primary T cells in vitro, STAT5B Y665F showed gain-of-function, whereas STAT5B Y665H demonstrated loss-of-function. Introducing the mutation into the mouse genome illustrated that the gain-of-function Stat5b Y665F mutation resulted in accumulation of CD8 + effector and memory and CD4 + regulatory T cells, altering CD8 + /CD4 + ratios. In contrast, STAT5B Y665H “knock-in” mice showed diminished CD8 + effector and memory and CD4 + regulatory T cells. In contrast to WT STAT5B, the STAT5B Y665F variant displayed greater STAT5 phosphorylation, DNA binding, and transcriptional activity after cytokine activation, whereas the STAT5B Y665H variant resembled a null. The work exemplifies how joining in silico and in vivo studies of single nucleotides deepens our understanding of disease-associated variants, revealing structural determinants of altered function, defining mechanistic roles, and, specifically here, identifying a gain-of-function variant that does not directly induce hematopoietic malignancy.","journal":"Life Science Alliance","year":2025,"id":520953,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1390844,"name":"Jichun Chen","orcid":"0000-0002-1038-471X","position":1,"is_corresponding":false},{"id":677208,"name":"Rachael L. Philips","orcid":"0000-0001-5440-4594","position":2,"is_corresponding":false},{"id":1331966,"name":"Sung‐Gwon Lee","orcid":"0000-0002-0928-9950","position":3,"is_corresponding":false},{"id":331112,"name":"Xingmin Feng","orcid":"0000-0001-8018-2366","position":4,"is_corresponding":false},{"id":218227,"name":"Zhijie Wu","orcid":"0000-0003-3984-0819","position":5,"is_corresponding":false},{"id":550267,"name":"Chengyu Liu","orcid":"0000-0003-1965-3020","position":6,"is_corresponding":false},{"id":1134531,"name":"Aaron B. Schultz","orcid":null,"position":7,"is_corresponding":false},{"id":1332356,"name":"Molly Dalzell","orcid":null,"position":8,"is_corresponding":false},{"id":323648,"name":"Manja Meggendorfer","orcid":"0000-0002-9038-3265","position":9,"is_corresponding":false},{"id":623973,"name":"Claudia Haferlach","orcid":"0000-0002-6333-5049","position":10,"is_corresponding":false},{"id":811153,"name":"Foster Birnbaum","orcid":"0000-0002-6062-2296","position":11,"is_corresponding":false},{"id":1331967,"name":"Joseph Sexton","orcid":"0000-0002-7072-6283","position":12,"is_corresponding":false},{"id":261779,"name":"Amy E. Keating","orcid":"0000-0003-4074-8980","position":13,"is_corresponding":false},{"id":291946,"name":"John J. O’Shea","orcid":"0000-0002-6456-9752","position":14,"is_corresponding":false},{"id":218269,"name":"Neal S. Young","orcid":"0009-0007-0999-2519","position":15,"is_corresponding":false},{"id":291945,"name":"Alejandro V. Villarino","orcid":"0000-0001-8068-2176","position":16,"is_corresponding":false},{"id":576168,"name":"Priscilla A. Furth","orcid":"0000-0003-3883-0715","position":17,"is_corresponding":false},{"id":14888,"name":"Lothar Hennighausen","orcid":"0000-0001-8319-9841","position":18,"is_corresponding":false},{"id":279569,"name":"Hye‐Kyung Lee","orcid":"0000-0002-7785-5942","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:49:32.958846Z","pmid":"40228864","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":[]}