PROJECT 1 ABSTRACT PI: Ross Levine, MD Primary myelofibrosis (MF) and progression of polycythemia vera (PV) and essential thrombocytosis (ET) to MF represent the most pressing clinical needs of patients with myeloproliferative neoplasms (MPNs), given that MF patients develop progressive cytopenias, splenomegaly, bone marrow fibrosis, disabling systemic symptoms and/or transformation to a treatment refractory form of acute leukemia, termed MPN-blast phase. The identification of somatic activating mutations involving the JAK2, MPL and CALR genes in most MPN/MF patients has underscored the role of constitutive JAK-STAT signaling in MF pathogenesis and has led to the clinical development of JAK2 inhibitors as the standard of care for MF patients. Clinical experience with currently available JAK2 inhibitors has shown that these agents can reduce cytokine production and attenuate MPN symptoms but are not capable of inducing either pathologic or molecular responses in most patients. Our recent work has uncovered a role for key epigenetic and inflammatory pathways in MF pathogenesis, which cooperate with activated JAK-STAT signaling to drive clinical progression and adverse outcomes in MF patients. These newly identified epigenetic and inflammatory pathways provide mechanistic insights into MPN disease pathogenesis and have the potential to serve as targets for the development of novel MF therapeutic approaches. We propose to investigate the role of aberrant epigenetic/inflammatory effector pathways in MF pathogenesis and to identify novel therapeutic targets which cooperate with JAK2 inhibition to increase therapeutic efficacy. The studies in this project will leverage novel, genetically accurate murine models of the most common MPN genotypes, coupled with detailed genomic, epigenomic, and therapeutic studies of primary samples from the MPN-RC Tissue Bank (Core B). Most importantly, the studies in this project are aimed to develop and credential novel therapeutic approaches that can then be transitioned to the clinic for mechanism based clinical trials in collaboration with Project 4 and the entire MPN-RC.