{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T19:42:55Z","timestamp":1771616575439,"version":"3.50.1"},"reference-count":76,"publisher":"American Society of Hematology","issue":"12","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Tight regulation of IL-7R\u03b1 expression is essential for normal T-cell development. IL-7R\u03b1 gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7R\u03b1 overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7R\u03b1 in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K\/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK\/STAT, PI3K\/Akt\/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R\u2013mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K\/mTOR), palbociclib (Cdk4\/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7\u2013stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7R\u03b1 can promote T-cell tumorigenesis, even in the absence of IL-7R\u03b1 mutational activation.<\/jats:p>","DOI":"10.1182\/blood.2019000553","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T21:00:26Z","timestamp":1620680426000},"page":"1040-1052","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":52,"title":["Overexpression of wild-type IL-7R\u03b1 promotes T-cell acute lymphoblastic leukemia\/lymphoma"],"prefix":"10.1182","volume":"138","author":[{"given":"Ana","family":"Silva","sequence":"first","affiliation":[{"name":"Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom;"},{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4292-8558","authenticated-orcid":false,"given":"Afonso R. M.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;"}]},{"given":"Ana","family":"Cachucho","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0863-158X","authenticated-orcid":false,"given":"Jo\u00e3o L.","family":"Neto","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8193-5734","authenticated-orcid":false,"given":"Sofie","family":"Demeyer","sequence":"additional","affiliation":[{"name":"Vlaams Instituut voor Biotechnologie (VIB) Center for Cancer Biology;"},{"name":"Katholieke Universiteit (KU) Leuven Center for Human Genetics, Katholieke Universiteit (VIB-KU) Leuven, Leuven, Belgium;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4206-2854","authenticated-orcid":false,"given":"Mafalda","family":"de Matos","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;"}]},{"given":"Thea","family":"Hogan","sequence":"additional","affiliation":[{"name":"Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5697-1602","authenticated-orcid":false,"given":"Yunlei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6860-798X","authenticated-orcid":false,"given":"Jules","family":"Meijerink","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Utrecht, The Netherlands.; and"}]},{"given":"Jan","family":"Cools","sequence":"additional","affiliation":[{"name":"Vlaams Instituut voor Biotechnologie (VIB) Center for Cancer Biology;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6974-4209","authenticated-orcid":false,"given":"Ana Rita","family":"Grosso","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias da Vida, Faculdade de Ci\u00eancias e Tecnologia, Unidade de Ci\u00eancias Biomoleculares Aplicadas (UCIBIO), Universidade NOVA de Lisboa, Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4352-3373","authenticated-orcid":false,"given":"Benedict","family":"Seddon","sequence":"additional","affiliation":[{"name":"Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom;"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4826-8976","authenticated-orcid":false,"given":"Jo\u00e3o 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