IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation
We previously reported that NOD.<i>Scid</i> 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...
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MDPI AG
2023-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/3/671 |
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| author | Madhuparna Nandi Amit Ghosh Sara Ali Akbari Diwakar Bobbala Marie-Josée Boucher Alfredo Menendez Trang Hoang Subburaj Ilangumaran Sheela Ramanathan |
| author_facet | Madhuparna Nandi Amit Ghosh Sara Ali Akbari Diwakar Bobbala Marie-Josée Boucher Alfredo Menendez Trang Hoang Subburaj Ilangumaran Sheela Ramanathan |
| author_sort | Madhuparna Nandi |
| collection | DOAJ |
| description | We previously reported that NOD.<i>Scid</i> 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 <i>Scid</i> 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.<i>Scid.Il15<sup>−/−</sup></i> mice prior to T-ALL development revealed discernible changes within the CD4<sup>−</sup>CD8<sup>−</sup> double-negative (DN) thymocyte developmental stages and increased frequencies of CD4<sup>+</sup>CD8<sup>+</sup> double-positive cells with a high proportion of TCR-negative CD4<sup>+</sup> and CD8<sup>+</sup> 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.<i>Scid</i> and C57BL/6.<i>Scid</i> mice displayed increased NOTCH1 activation that was inhibited by NOTCH1 inhibitors and blockers of the PI3K/AKT pathway. Primary leukemic cells from NOD.<i>Scid.Il15<sup>−/−</sup></i> 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. |
| first_indexed | 2024-03-11T09:51:01Z |
| format | Article |
| id | doaj.art-627ba32e87fc4ef092419b2e82ce2767 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:51:01Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-627ba32e87fc4ef092419b2e82ce27672023-11-16T16:15:29ZengMDPI AGCancers2072-66942023-01-0115367110.3390/cancers15030671IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 ActivationMadhuparna Nandi0Amit Ghosh1Sara Ali Akbari2Diwakar Bobbala3Marie-Josée Boucher4Alfredo Menendez5Trang Hoang6Subburaj Ilangumaran7Sheela Ramanathan8Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Medicine, Gastroenterology Unit, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaInstitute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 1K3, CanadaDepartment of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaWe previously reported that NOD.<i>Scid</i> 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 <i>Scid</i> 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.<i>Scid.Il15<sup>−/−</sup></i> mice prior to T-ALL development revealed discernible changes within the CD4<sup>−</sup>CD8<sup>−</sup> double-negative (DN) thymocyte developmental stages and increased frequencies of CD4<sup>+</sup>CD8<sup>+</sup> double-positive cells with a high proportion of TCR-negative CD4<sup>+</sup> and CD8<sup>+</sup> 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.<i>Scid</i> and C57BL/6.<i>Scid</i> mice displayed increased NOTCH1 activation that was inhibited by NOTCH1 inhibitors and blockers of the PI3K/AKT pathway. Primary leukemic cells from NOD.<i>Scid.Il15<sup>−/−</sup></i> 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.https://www.mdpi.com/2072-6694/15/3/671T cell acute lymphoblastic leukemia<i>Scid</i>IL-15NOTCH1MS5-DL4 |
| spellingShingle | Madhuparna Nandi Amit Ghosh Sara Ali Akbari Diwakar Bobbala Marie-Josée Boucher Alfredo Menendez Trang Hoang Subburaj Ilangumaran Sheela Ramanathan IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation Cancers T cell acute lymphoblastic leukemia <i>Scid</i> IL-15 NOTCH1 MS5-DL4 |
| title | IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation |
| title_full | IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation |
| title_fullStr | IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation |
| title_full_unstemmed | IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation |
| title_short | IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation |
| title_sort | il 15 prevents the development of t all from aberrant thymocytes with impaired dna repair functions and increased notch1 activation |
| topic | T cell acute lymphoblastic leukemia <i>Scid</i> IL-15 NOTCH1 MS5-DL4 |
| url | https://www.mdpi.com/2072-6694/15/3/671 |
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