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. ABSTRACT: 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.