Ricerc@Sapienza

Acute T-cell lymphoblastic leukemia (T-ALL) is a childhood cancer, characterized by the infiltration of immature T-cells in the bone marrow. Aberrant Notch signaling has been implicated in the development of different human cancers, including T-ALL. T-ALL cases very frequently bear somatic gain-of-function gene mutations in Notch1, as well as overexpression of Notch3. Moreover, Notch3 gene activating mutations have been recently described in T-ALL patients. Although, Notch hyperactivation is known to be a major driver of T-ALL development, the nature of malignant lymphoblasts expressing immature T-cells markers, but capable to escape thymus retention and infiltrate the bone marrow are still unclear. These cells could possibly represent ¿pre-leukemic¿ cells and the mechanisms underlying their dissemination need to be clarified.
The aim of our study is the analysis of the early intrathymic progenitors in a Notch3 transgenic mouse model, which recapitulates some of the features of human T-ALL. We want to focus our attention on double negative T-cells (CD4-CD8-, DN) by analysing the presence of a chemokine receptor, CXCR4, known to be highly expressed in CD25+ T-cells and known to play a role in T-cell differentiation. To this end, flow cytometry analysis will be performed to analyze the expression of this chemokine receptor in all four DN subpopulations (DN1-4). To define the possible modulation of CXCR4 in these cells we will perform transcriptional and post-trascriptional analysis in order to unveil new molecular mechanisms in T-ALL biology.
Final purpose of the present research plan will be to identify early immature T-cell deregulated processes, that might influence the following progressive stages of T-cell development driving to T-cell leukemia. In so doing, we would correlate the identity of these cells with diagnosis and relapse of the disease and to open new opportunities for the treatment of T-ALL.