NOTCH SIGNALING DEREGULATION IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA PROMOTES THE GENERATION OF MYELOID DERIVED SUPPRESSOR CELLS

Notch receptors play an important role in both T cell differentiation and T-cell leukemia development. Notch3 constitutive activation inside T cell compartment of transgenic (N3tg) mice induces an aggressive form of ‘T-cell acute lymphoblastic leukemia’ (T-ALL), characterized by the ‘aberrant’ presence of extrathymic immature CD4+CD8+ T cells. ‘Myeloid Derived Suppressor Cells’ (MDSCs) include a heterogeneous group of immature/progenitor myeloid cells, that in mice are broadly identified as CD11b+Gr-1+ cells. MDSCs are expanded and activated in tumor microenvironment, where they suppress host immune responses, including that of T cells, thus facilitating disease progression. MDSCs have been extensively described in solid tumors and, more recently in hematological malignancies. However, nothing is known about MDSCs in acute T-cell leukemia, so far. We observed alterations inside myeloid compartment of N3-tg mice, with a systemic expansion of immature CD11b+Gr1+ cells, that display features of MDSCs, such as the overexpression of molecules involved in their functios (i.e. Arginase-1, ROS), and the ability to suppress in vitro proliferating T cells. To the best of our knowledge, this represents the first demonstration of the presence of MDSCs in associaton with T-cell leukemia. Moreover, we suggest that in our model of Notch3-dependent T-ALL, the massive presence of aberrant CD4+CD8+ (DP) T cells in BM ‘tumor’ microenvironment induces alterations in differentiation of myeloid compartment, through a non-cell autonomous mechanism. Indeed, BM CD4+CD8+ T cells from N3-tg mice promote the generation of MDSCs, at least in vitro, through a mechanism that is partially dependent on the IL-6 produced. Collectively, our data shed new light on the cross-talk between T cell and myeloid cell compartment and report the appearence of MDSCs in the context of Notch-dependent T-ALL, that may influence the disease outcome and thus would have an important impact on the development of innovative therapies