Publication
Transgenic αβ TCR tonic signaling is leukemogenic while strong stimulation is leukemia suppressive
| dc.contributor.author | Catarino, Telmo A. | |
| dc.contributor.author | Pacheco-Leyva, Ivette | |
| dc.contributor.author | Baessa, Marina | |
| dc.contributor.author | Pereira, João L. | |
| dc.contributor.author | Rodrigues dos Santos, Nuno | |
| dc.date.accessioned | 2025-01-15T14:35:15Z | |
| dc.date.available | 2025-01-15T14:35:15Z | |
| dc.date.issued | 2024-11-22 | |
| dc.description.abstract | The pre–T cell receptor (TCR) and TCR complexes are frequently expressed in T cell acute lymphoblastic leukemia (T-ALL), an aggressive T cell precursor malignancy. Although mutations in TCR components are infrequent in T-ALL, earlier research indicated that transgenic αβ 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 αβ TCR complex has a dual role in leukemogenesis depending on the nature of the stimulus. We demonstrate that transgenic expression of the Marilyn αβ 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 β2-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 αβ TCR complex in T-ALL, in which tonic stimulation is leukemogenic, while strong stimulation suppresses leukemia. | eng |
| dc.description.sponsorship | POCI-01-0145-FEDER-007274; PTDC/MED-ONC/32592/2017; NORTE-01-0145-FEDER- 000029; PD/BD/114129/2015; 2021.06024.BD | |
| dc.identifier.doi | 10.1093/jleuko/qiae249 | |
| dc.identifier.issn | 1938-3673 | |
| dc.identifier.uri | http://hdl.handle.net/10400.1/26629 | |
| dc.language.iso | eng | |
| dc.peerreviewed | yes | |
| dc.publisher | Oxford University Press | |
| dc.relation | PSGL-1 inactivation: A two-prong strategy to target lymphoma | |
| dc.relation.ispartof | Journal of Leukocyte Biology | |
| dc.rights.uri | N/A | |
| dc.subject | Cdkn2a | |
| dc.subject | Notch1 | |
| dc.subject | Leukemia | |
| dc.subject | T cells | |
| dc.subject | TCR signaling | |
| dc.title | Transgenic αβ TCR tonic signaling is leukemogenic while strong stimulation is leukemia suppressive | eng |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | PSGL-1 inactivation: A two-prong strategy to target lymphoma | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017/PTDC%2FMED-ONC%2F32592%2F2017/PT | |
| oaire.citation.title | Journal of Leukocyte Biology | |
| oaire.fundingStream | Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017 | |
| oaire.version | http://purl.org/coar/version/c_ab4af688f83e57aa | |
| person.familyName | Rodrigues dos Santos | |
| person.givenName | Nuno | |
| person.identifier.orcid | 0000-0001-7347-2592 | |
| person.identifier.scopus-author-id | 7006810054 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
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