Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis. It has the worst prognosis among the three types of MPN, and a dearth of effective treatment options. Calreticulin (CALR) mutations account for ~40% of MPN cases, and are categorized as type 1 or type 2. Clinically, type 1 mutations are associated with MF, while type 2 mutations are restricted to a more indolent and treatable MPN, essential thrombocythemia. Here, Shannon Elf and her group will test the hypothesis that type 1 CALR mutations cause myelofibrosis by activating a complex signaling axis in the bone marrow. They posit that type 1 CALR mutations cause altered calcium homeostasis that provoke an endoplasmic reticulum (ER) stress response, which ultimately induces cross talk between megakaryocytes and the stromal cells of the bone marrow to increase collagen production. In this work, they will test whether this dysregulation is mediated by a number of converging pathways, including the IRE1α-XBP1 unfolded protein response, TGFβ signaling, and the mTORC1-ATF4 axis. Ultimately, these studies will examine whether targeting this network of pathways represents an effective therapy for type 1 CALR+ myelofibrosis.