| First Author | Nandi M | Year | 2023 |
| Journal | Cancers (Basel) | Volume | 15 |
| Issue | 3 | PubMed ID | 36765626 |
| Mgi Jnum | J:333331 | Mgi Id | MGI:7435872 |
| Doi | 10.3390/cancers15030671 | Citation | Nandi M, et al. (2023) IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation. Cancers (Basel) 15(3) |
| abstractText | 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(-/-) mice prior to T-ALL development revealed discernible changes within the CD4(-)CD8(-) 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(-/-) 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. |
