Project summary/Abstract Understanding and targeting abnormal tumor microenvironment is critically important for developing effective therapy. Primary myelofibrosis (PMF) is a form of myeloproliferavtie neoplasm (MPN) that often progresses to lethal leukemia. Treatment options are limited for PMF, and the only potential cure, stem cell transplantation, is prohibitively toxic for most patients. Thus, novel and effective therapies are in great need for PMF. Recurrent mutations resulting in abnormal activation of the JAK-STAT pathway have been shown to be the driver of the disease. As a result, JAK inhibitors have been developed to treat PMF. However, these inhibitors only reduce some constitutional symptoms without significant impact on disease-causing leukemia stem cells (LSCs). A deeper understanding of the pathogenesis of PMF will offer the opportunity to better treat the disease. The bone marrow niche is a critical component to the pathogenesis of PMF. Our preliminary data show that bone marrow LepR+ stromal cells are the source of fibrosis. We have also identified several key mediators of LepR+ cell fibrosis. In this proposal, we propose to elucidating the cellular and molecular mechanisms of how LSCs interact with the fibrotic niche in vivo. We will test whether targeting the fibrosis mediators will lead to efficient elimination of LSCs and have synergistic effects with JAK inhibitors. By having a deeper understanding of the interaction between LSCs and the niche, our strategy of targeting the diseased niche may provide novel therapeutics to PMF.