Targeting of IL-1 Signaling in Myelofibrosis

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Title: Targeting of IL-1 Signaling in Myelofibrosis PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are a group of clonal hematopoietic stem cell derived myeloid malignancies characterized by overproduction of myeloid lineage cells. MF is the deadliest among MPNs. The median survival of patients with MF is ~5 years. The oncogenic JAK2V617F mutation was found in ~95% cases of PV and ~50-60% cases of ET and MF. Mutations in the thrombopoietin receptor (MPL) and calreticulin (CALR) were also detected in MF. Currently approved JAK inhibitors, Ruxolitinib and Fedratinib, can alleviate constitutional symptoms but they do not offer significant improvement of bone marrow fibrosis. Therefore, there is an unmet need to identify new therapeutic targets and develop novel therapies for MF. Chronic inflammation is frequently associated with MPN/MF. Expression of interleukin-1 (IL-1), a master regulator of inflammation, is found elevated in MPN/MF patients as well as in Jak2V617F knock-in mice. However, the contribution of IL-1 signaling in the pathogenesis of MPN/MF has remained elusive. In preliminary studies, we have found that genetic deletion of IL-1R1 normalizes peripheral blood counts, reduces splenomegaly and significantly inhibits bone marrow fibrosis in a Jak2V617F knock-in mouse model of MF. So, we hypothesize that IL-1 signaling may play an important role in the pathogenesis of MF and targeting of IL-1 signaling might be useful for treatment of MF. In this proposal, we will further investigate the contribution of IL-1 signaling in the pathogenesis of MF and test the efficacy of pharmacologic inhibition of IL-1 signaling in pre-clinical models of myelofibrosis. We will also determine the mechanism by which inhibition of IL-1 signaling prevents the progression of MPN/MF. Results from this study may lead to new therapeutic approach for treatment of myelofibrosis.