Experimental activities carried out over the course of the action produced a significant amount of data coherently pointing towards the ability of FOXO1 mutations to rewire signaling activities in MYC-driven B cell lymphomas, to ultimately favor the acquisition of improved fitness, particularly in BCR-less cells, as demonstrated combining biochemical and cellular assays. Cellular mechanisms underlying the competitive advantage promoted by FOXO1 mutations in BCR-dependent lymphomas have been in part disclosed and reconducted to a reduced sensitivity to stress-induced apoptosis. It is also relevant to highlight that this effect was not strictly associated with BCR-deprived lymphomas, as it was also observed independently of BCR-expression, potentially allowing to extend these findings to a broader spectrum of B-cell malignancies (and not only those whose pathogenesis relates to the biology of the BCR). Results generated during the action are currently being further confirmed in a) at least 3 independent mouse lymphoma lines, retrovirally engineered to express FOXO1 mutations; b) CRISPR-Cas9 genetically engineered mouse MYC-driven lymphoma lines carrying FOXO1 Gain-of-Function (GOF) or Loss-of-function (LOF) mutations, and c) in human primary tonsil-derived germinal center B cells, immortalized upon enforced expression of specific oncogenic combinations (i.e. MYC/BCL2/BCL6). These cellular models have been generated within the timeframe of the action, and will represent an invaluable platform to address biologically relevant questions in the field of B-cell lymphomagenesis. Data generated during the action using these cellular models suggested a dual contribution of the BCR in the pathogenesis of B cell lymphoma, highlighting a cell autonomous regulation of lymphoma growth ensuring cellular fitness, while favoring tumor expansion in vivo hampering immune-recognition of lymphoma B cells, through the regulation of immune-related receptors, providing a roadmap to disclose mechanistic insights explaining differential in vivo dynamics of expansion and growth rates between BCR+ and BCR-deficient lymphomas. These observations become particularly relevant given the increasing genetic/genomic data on primary B-cell malignancies confirming the presence of FOXO1 mutations in a variety of B-cell lymphomas, characterized by different cell-of-origin, BCR-status and/or genetic/molecular features. As part of our dissemination plan, a manuscript describing these results is currently in preparation. Moreover, findings with some commercial potential will be intellectually protected and economically exploited thanks to the support of the Technology Transfer Office at IFOM-ETS. Finally, results stemming from this project have already been inspirational for the generation of novel hypothesis-driven research activities, which have been exploited for the preparation of competitive grant applications, one of which (American Society of Hematology, Global Research Award) has been already funded. Dissemination and outreach activities towards both scientific (through the attendance to national and international workshops, meetings and conferences to share our most recent advancements) and non-scientific communities (public outreach in schools, social media, in-person interactive events involving local communities with diverse social and educational backgrounds) have been extensively carried out throughout the action.
