{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:18:17Z","timestamp":1790421497187,"version":"4.1.0"},"reference-count":103,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cancer Research Society","award":["24025"],"award-info":[{"award-number":["24025"]}]},{"name":"Fonds de Recherche de Qu\u00e9bec en Sant\u00e9 (FRQS)","award":["24025"],"award-info":[{"award-number":["24025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>We previously reported that NOD.Scid mice lacking interleukin-15 (IL-15), or IL-15 receptor alpha-chain, develop T-acute lymphoblastic leukemia (T-ALL). To understand the mechanisms by which IL-15 signaling controls T-ALL development, we studied the thymocyte developmental events in IL-15-deficient Scid mice from NOD and C57BL\/6 genetic backgrounds. Both kinds of mice develop T-ALL characterized by circulating TCR-negative cells expressing CD4, CD8 or both. Analyses of thymocytes in NOD.Scid.Il15\u2212\/\u2212 mice prior to T-ALL development revealed discernible changes within the CD4\u2212CD8\u2212 double-negative (DN) thymocyte developmental stages and increased frequencies of CD4+CD8+ double-positive cells with a high proportion of TCR-negative CD4+ and CD8+ cells. The DN cells also showed elevated expressions of CXCR4 and CD117, molecules implicated in the expansion of DN thymocytes. T-ALL cell lines and primary leukemic cells from IL-15-deficient NOD.Scid and C57BL\/6.Scid mice displayed increased NOTCH1 activation that was inhibited by NOTCH1 inhibitors and blockers of the PI3K\/AKT pathway. Primary leukemic cells from NOD.Scid.Il15\u2212\/\u2212 mice survived and expanded when cultured with MS5 thymic stromal cells expressing Delta-like ligand 4 and supplemented with IL-7 and FLT3 ligand. These findings suggest that IL-15 signaling in the thymus controls T-ALL development from aberrant thymocytes with an impaired DNA repair capacity and increased NOTCH1 activation.<\/jats:p>","DOI":"10.3390\/cancers15030671","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T04:19:22Z","timestamp":1674447562000},"page":"671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation"],"prefix":"10.3390","volume":"15","author":[{"given":"Madhuparna","family":"Nandi","sequence":"first","affiliation":[{"name":"Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4017-6513","authenticated-orcid":false,"given":"Sara Ali","family":"Akbari","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diwakar","family":"Bobbala","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Jos\u00e9e","family":"Boucher","sequence":"additional","affiliation":[{"name":"Department of Medicine, Gastroenterology Unit, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Menendez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trang","family":"Hoang","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 1K3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-576X","authenticated-orcid":false,"given":"Subburaj","family":"Ilangumaran","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheela","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMra023001","article-title":"Acute lymphoblastic leukemia","volume":"350","author":"Pui","year":"2004","journal-title":"N. 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