The transcription factor MAF and Toll-like Receptors as key players in the inflammatory and pro-fibrotic landscape of myelofibrosis

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by the development of bonemarrow (BM) fibrosis, chronic non-resolving inflammation, leukemic progression and shortenedlife expectancy. The abnormal release of profibrotic and proinflammatory mediators by theneoplastic cells fosters the development of BM fibrosis and chronic inflammation in MF patients.None of the genomic lesions identified is able to recapitulate in animal models all the features ofMF pathogenesis, especially the BM fibrosis. In addition, the treatment with ruxolitinib does notabrogate cytokine overproduction and does not reverse BM fibrosis in MF patients. We have demonstrated that the expression of the oncogenic transcription factor avianmusculoaponeurotic fibrosarcoma (MAF) is remarkably increased in MF hematopoietic progenitorcells (HPCs) and fuels the release of many mediators of inflammation and fibrosis that areoverproduced in MF patients. However, the mechanisms responsible for MAF overexpression inMF patients still remain largely unknown. To gain further insights into the mechanisms driving theoverproduction of mediators in MF, we have performed a computational prediction of thepathways whose activation would be responsible for the transcriptional differences between MFand healthy donor HPCs. Toll Like Receptors (TLRs) –especially endosomal TLR3, TLR7 andTLR9 - pathways were predicted as hyper-activated in MF HPCs pointing out their involvement inthe cytokine storm that accompany the development of BM fibrosis. Therefore, in this project two group leaders with complementary expertise in pathobiologicalmechanisms of myelofibrosis will jointly test the hypothesis that MAF and TLRs are key players inthe inflammatory and pro-fibrotic landscape of MF. We therefore aim: 1) to study whether theexpression of MAF can recapitulate in vivo key features of MF not reproduced by current mousemodels and to assess whether MAF is a novel druggable target in MF and 2) to unravel the roleof TLR3, TLR7 and TLR9 in the overproduction of proinflammatory and profibrotic mediators byMF cells and evaluate whether they are actionable targets. The role of MAF in MF pathogenesiswill be dissected through its overexpression in vitro and in vivo, in JAK2V617F mice. The effectsof inhibitors of pathways that are known to affect MAF expression or function will be evaluated invitro in HPCs. Moreover, in vitro and in vivo contribution of individual TLRs to the pathogenesis ofMF will be evaluated in MF HPCs and in a Romiplostim-induced MF model, respectively. We envision that this integrated strategy will unveil the involvement of MAF and TLR3, TLR7 andTLR9 signaling pathways in the pathogenesis of MF, and especially in the release ofinflammatory and profibrotic stimuli. These achievements will shed light onto the mechanismsunderlying the pathogenesis