Key Points Calreticulin mutants responsible for myeloproliferative neoplasms specifically activate the thrombopoietin receptor and in turn JAK2. Activation of the thrombopoietin receptor requires the glycan binding site and a novel C-terminal tail of the mutant calreticulin.

Key Points Calreticulin type I and type II mutants are drivers of the disease as they induce thrombocytosis in a retroviral mouse model. Thrombopoietin receptor MPL is required for calreticulin mutants to induce an essential thrombocythemia phenotype in transplanted mice.