IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation

Simple Summary Leukemia is a diverse group of hematopoietic malignancies that cause significant morbidity and mortality in children and adults. Although intensive chemotherapy can cure the majority of T-ALL cases, chemo-resistant and relapse cases have poor prognoses. Treatment of such cases requires the development of new approaches through a greater understanding of the molecular mechanisms of leukemogenesis. We have previously reported the spontaneous development of T-ALL in mice with impaired IL-15 signaling caused by IL-15 or IL-15 receptor deficiency. In this study, we examined the thymocyte developmental changes that precede leukemogenesis in these mice. Our findings reveal that IL-15 deficiency yields the expansion of aberrant TCR-negative T cells that may arise from impaired DNA repair in developing thymocytes. In addition, we show that these pre-leukemic cells display increased NOTCH1 activation and rely on survival signals provided by cytokines and growth factors, which may also be required for leukemogenesis. 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.