MPL encodes the thrombopoietin receptor, an important growth and survival factor for megakaryocytes. Somatic activating mutation in MPL (W515L, W515K) has been reported in approximately 1%-10% of cases of JAK2 V617F-negative myelofibrosis, essential thrombocythemia, a subset of cases of acute megakaryoblastic leukemia and has been associated with sensitivity to JAK inhibitors. The W515 mutations are typically not observed in polycythemia vera or other myeloid disorders (chronic myelomonocytic leukemia, myelodysplastic syndrome). A S505N activating mutation has also been described in familial essential thrombocythemia. MPL mutation is included as one of the major diagnostic criteria for primary myelofibrosis and essential thrombocythemia in the 2016 revision of the WHO classification.