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.

This gene is a known cancer gene.

This gene is a known cancer gene.

This MPL variant has been previously reported in the COSMIC database (COSM28997) and has been reported to be an activating mutation (PubMed ID: 26423830, Milosevic Feenstra et al., Blood 2016).

The MPL p.S505N mutation is a recurrent mutation in some myeloproliferative and/or myeloproliferative/myelodysplastic disorders. It has also been reported in familial essential thrombocythemia. Biochemical studies of this variant have shown that it leads to moderate activation of downstream pathways including MEK-1/-2 and STAT5, which represent potentially targetable pathways.