"Dissecting the role of the proto-oncogene MAF and the pathways that fuel fibrosis and inflammation in myelofibrosis"

Background Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by the development of bone marrow (BM) fibrosis, chronic non-resolving inflammation, leukemic progression and shortened life expectancy. The abnormal release of profibrotic and proinflammatory mediators by the neoplastic cells fosters the development of BM fibrosis and chronic inflammation in MF patients. None of the genomic lesions identified is able to recapitulate all the features of MF pathogenesis and especially the BM fibrosis. In addition, the treatment with ruxolitinib does not abrogate cytokine overproduction and does not reverse BM fibrosis in MF patients. Hypothesis We have demonstrated that the expression of the oncogenic transcription factor avian musculoaponeurotic fibrosarcoma (MAF) is remarkably increased in MF cells and fuels the release of many mediators of inflammation and fibrosis that are overproduced in MF patients. We therefore hypothesize that Maf could be involved in MF pathogenesis. To identify the mechanisms driving the abnormal expression of MAF and the overproduction of mediators in MF, we have performed a computational prediction of the pathways whose activation would be responsible for the transcriptional differences between MF and healthy donors cells. We hypothesize that these pathways could fuel the cytokine storm and the development of BM fibrosis. Aims We aim: 1) to study whether the expression of Maf could recapitulate in vivo key features of MF not reproduced by current mouse models; 2) to investigate the mechanisms that foster Maf overexpression and assess whether Maf is a novel druggable target in MF and 3) to unravel the contribution of selected pathways to the overproduction of proinflammatory and profibrotic mediators by MF cells and to evaluate whether they are actionable targets. Experimental Design The role of Maf in MF pathogenesis will be assessed through the analysis of the effects of Maf overexpression in vitro and in vivo, in established MPN mouse models. The mechanisms underlying the overexpression of Maf in MF will be assessed by the screening of inhibitors of Maf expression or function in vitro and, for drugs endowed with a potential of clinical use, in vivo in MF patient-derived xenotransplantation (PDX) models. The activity of selected signaling pathways will be characterized in cells from MF patients and their contribution to the pathogenesis of MF will be assessed in vitro and in vivo in MPN mouse models. For the emerging pathways, inhibitors endowed with a potential of clinical use will be evaluated in vitro and in vivo in MF PDX models. Expected Results We will elucidate the involvement of Maf and selected signaling pathways in the pathogenesis of MF, and especially the overproduction of proinflammatory and profibrotic mediators. Furthermore, we will provide in vitro and in vivo evidence of whether and how Maf and selected signaling pathways are novel actionable targets in MF. Impact On Cancer The insights gained from this project will shed light onto the mechanisms underlying the pathogenesis of a still uncurable disease. These achievements will lead to the characterization of novel druggable targets and, presumably, to the identification of specific inhibitors endowed with a potential of clinical use to improve the current therapies for MF.