Ricerc@Sapienza

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10%-15% of pediatric and 25% of adult ALL cases. The disease is critically associated to Notch signaling deregulation, since about 60% of T-ALL harbor activating NOTCH1 mutations and the vast majority of T-ALL patients displays increased expression and function of Notch3. Current treatments fail in 20-30% of T-ALL patients and Notch signaling may contribute to chemotherapy resistance, thus suggesting Notch inhibition as a targeted therapy strategy.
We and others previously reported that the development of T-ALL in mouse models is preceded by the appearence in periphery of CD4+CD8+ "preleukemic cells", which may mirror the disruption of normal intrathymic T cell differentiation, that in turn may represent the primum movens of T-ALL development, at least of the childhood disease. This proposal is designed to gain mechanistic and functional insights into the effects of Notch signaling deregulation in intrathymic T cell differentiation, which may lead to T-ALL development through the disruption of normal relationships between T cell precursors and the microenvironment. Our main goals are: i) to identify the mechanisms underlying the thymus egression of "pre-leukemic cells" and to follow their fate in the periphery in order to define a possible hierarchical colonization program; ii) to dissect their relationships with the different microenvironments, encountered during initiation, development and/or relapse of the disease. The dissection of cellular and molecular mechanisms, involved in the crosstalk between leukemia cells at different stages and microenvironment of different districts, may
help future research aimed to identify malignant niches where pre-leukemic cells may receive instructive cues for their maintenance, as leukemia initiating cells (i.e. cancer stem cells), or evolve from preleukemic to leukemic stages in the course of the disease, finally supporting the design of novel target therapy protocols.