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Although mutations in TCR components are infrequent in T-ALL, earlier research indicated that transgenic \u03b1\u03b2 TCR expression in mouse T cell precursors promoted T-ALL development. However, we recently found that stimulation of TCR signaling in T-ALL induced leukemic cell apoptosis and suppressed leukemia. Our aim was to elucidate if a given \u03b1\u03b2 TCR complex has a dual role in leukemogenesis depending on the nature of the stimulus. We demonstrate that transgenic expression of the Marilyn \u03b1\u03b2 TCR, specific for the H-Y male antigen presented by major histocompatibility complex class II, triggers T-ALL development exclusively in female mice. This T-ALL exhibited Notch1 mutations, Cdkn2a copy number loss, and immature immunophenotype, and infiltrated both lymphoid and nonlymphoid organs. Furthermore, leukemic cells expressed surface CD5, a marker of tonic TCR signaling. T-ALL efficiently developed in Rag2-deficient Marilyn transgenic females, indicating that Rag2-mediated recombination is not implicated in this T-ALL model. T-ALL development was also observed in the OT-I TCR transgenic mouse model, but it did not occur when major histocompatibility complex class I was abrogated through genetic inactivation of \u03b22-microglobulin. Remarkably, exposure of Marilyn female T-ALL cells to endogenous agonist antigens in male recipient mice or exogenous peptides in female recipient mice resulted in T-ALL apoptosis and prolonged mouse survival. These findings underscore the dual role of the same \u03b1\u03b2 TCR complex in T-ALL, in which tonic stimulation is leukemogenic, while strong stimulation suppresses leukemia.<\/jats:p>","DOI":"10.1093\/jleuko\/qiae249","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T07:19:37Z","timestamp":1732173577000},"source":"Crossref","is-referenced-by-count":0,"title":["Transgenic \u03b1\u03b2 TCR tonic signaling is leukemogenic while strong stimulation is leukemia suppressive"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2498-9648","authenticated-orcid":false,"given":"Telmo A","family":"Catarino","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto , Rua Alfredo Allen, 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), Universidade do Porto , Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto ,","place":["Portugal"]},{"name":"Graduate Program in Areas of Basic and Applied Biology, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto , Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-2264","authenticated-orcid":false,"given":"Ivette","family":"Pacheco-Leyva","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto , Rua Alfredo Allen, 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), Universidade do Porto , Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6760-7884","authenticated-orcid":false,"given":"Marina","family":"Baessa","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto , Rua Alfredo Allen, 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), Universidade do Porto , Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8625-5420","authenticated-orcid":false,"given":"Jo\u00e3o L","family":"Pereira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto , Rua Alfredo Allen, 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), Universidade do Porto , Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7347-2592","authenticated-orcid":false,"given":"Nuno","family":"R. dos Santos","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto , Rua Alfredo Allen, 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"Institute of Molecular Pathology and Immunology (IPATIMUP), Universidade do Porto , Rua J\u00falio Amaral de Carvalho, 45, 4200-135 Porto ,","place":["Portugal"]},{"name":"Centre for Biomedical Research (CBMR), University of Algarve , Campus de Gambelas, 8005-139 Faro ,","place":["Portugal"]}]}],"member":"286","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"issue":"9","key":"2025060413313889500_qiae249-B1","doi-asserted-by":"publisher","first-page":"4017","DOI":"10.4049\/jimmunol.1302259","article-title":"An overview of the intrathymic intricacies of T cell development","volume":"192","author":"Shah","year":"2014","journal-title":"J Immunol"},{"issue":"6","key":"2025060413313889500_qiae249-B2","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/nri3667","article-title":"Positive and negative 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