{"doi":"10.1073/pnas.2201493119","title":"Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation","abstract":"Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Here we show that leukemias induced by aberrant activation of β-catenin in thymocytes, which bear recurrent Tcra/Myc-Pvt1 translocations, depend on Tcf-1. The DNA double strand breaks (DSBs) in the Tcra site of the translocation are Rag-generated, whereas the Myc-Pvt1 DSBs are not. Aberrantly activated β-catenin redirects Tcf-1 binding to novel DNA sites to alter chromatin accessibility and down-regulate genome-stability pathways. Impaired homologous recombination (HR) DNA repair and replication checkpoints lead to retention of DSBs that promote translocations and transformation of double-positive (DP) thymocytes. The resulting lymphomas, which resemble human T cell acute lymphoblastic leukemia (T-ALL), are sensitive to PARP inhibitors (PARPis). Our findings indicate that aberrant β-catenin signaling contributes to translocations in thymocytes by guiding Tcf-1 to promote the generation and retention of replication-induced DSBs allowing their coexistence with Rag-generated DSBs. Thus, PARPis could offer therapeutic options in hematologic malignancies with active Wnt/β-catenin signaling.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":244901,"datarank":0.6485800656727796,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.1542045357721301,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.1542045357721301,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":13,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"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":878814,"name":"Priya Mathur","orcid":"0000-0003-0378-7171","position":1,"is_corresponding":false},{"id":715325,"name":"Melissa Tracy","orcid":"0000-0003-3209-0197","position":2,"is_corresponding":false},{"id":429035,"name":"Azam Mohsin","orcid":"0000-0003-0021-3244","position":3,"is_corresponding":false},{"id":878815,"name":"Soumi Mondal","orcid":"0009-0001-3804-6165","position":4,"is_corresponding":false},{"id":84982,"name":"Jasmin Quandt","orcid":null,"position":5,"is_corresponding":false},{"id":628424,"name":"Kyle M. Hernandez","orcid":"0000-0001-8267-644X","position":6,"is_corresponding":false},{"id":409816,"name":"Khashayarsha Khazaie","orcid":"0000-0002-7884-1817","position":7,"is_corresponding":false},{"id":878816,"name":"Marei Dose","orcid":"0000-0001-5394-9779","position":8,"is_corresponding":false},{"id":878817,"name":"Akinola Olumide Emmanuel","orcid":"0000-0003-0118-7818","position":9,"is_corresponding":false},{"id":563506,"name":"Fotini Gounari","orcid":"0000-0003-2936-066X","position":10,"is_corresponding":false},{"id":563505,"name":"Stephen Arnovitz","orcid":"0000-0001-5307-8694","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:23:30.364338Z","pmid":"35921443","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":[]}