{"doi":"10.1172/jci143950","title":"The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease","abstract":"Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.","journal":"Journal of Clinical Investigation","year":2022,"id":243382,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"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":443740,"name":"Yongxia Wu","orcid":"0000-0003-1568-2377","position":1,"is_corresponding":false},{"id":875174,"name":"Arjun Kharel","orcid":"0000-0002-4203-5469","position":2,"is_corresponding":false},{"id":444656,"name":"David Bastian","orcid":null,"position":3,"is_corresponding":false},{"id":639192,"name":"Hee-Jin Choi","orcid":"0000-0002-8834-2026","position":4,"is_corresponding":false},{"id":639876,"name":"M. Hanief Sofi","orcid":null,"position":5,"is_corresponding":false},{"id":639193,"name":"Corey Mealer","orcid":"0009-0007-9418-6895","position":6,"is_corresponding":false},{"id":875744,"name":"Brianyell McDaniel Mims","orcid":null,"position":7,"is_corresponding":false},{"id":443736,"name":"Hung Nguyen","orcid":"0000-0001-9416-5137","position":8,"is_corresponding":false},{"id":244937,"name":"Chen Liu","orcid":"0009-0003-0430-6146","position":9,"is_corresponding":false},{"id":451267,"name":"Kristi L. Helke","orcid":"0000-0001-9746-0764","position":10,"is_corresponding":false},{"id":302507,"name":"Weiguo Cui","orcid":"0000-0003-1562-9218","position":11,"is_corresponding":false},{"id":240584,"name":"Xian Zhang","orcid":"0000-0001-9674-7886","position":12,"is_corresponding":false},{"id":875175,"name":"Yaacov Ben‐David","orcid":"0000-0002-9020-6074","position":13,"is_corresponding":false},{"id":321624,"name":"Xue‐Zhong Yu","orcid":"0000-0002-1751-2884","position":14,"is_corresponding":false},{"id":443739,"name":"Steven Schutt","orcid":"0000-0002-2069-2556","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T00:23:16.032700Z","pmid":"36074578","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":[]}