This study investigates the molecular basis of myeloproliferative disorders in patients without the V617F mutation, which is commonly found in polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. The researchers identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. These patients presented with isolated erythrocytosis, distinctive bone marrow morphology, and reduced serum erythropoietin levels. Erythroid colonies from their blood samples could be grown without exogenous erythropoietin, and all such colonies were heterozygous for the mutation. The mutations included substitutions of leucine for lysine at position 539 of JAK2, which resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of bone marrow transplantation. The findings suggest that JAK2 exon 12 mutations define a distinct myeloproliferative syndrome that affects patients currently diagnosed with polycythemia vera or idiopathic erythrocytosis.This study investigates the molecular basis of myeloproliferative disorders in patients without the V617F mutation, which is commonly found in polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. The researchers identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. These patients presented with isolated erythrocytosis, distinctive bone marrow morphology, and reduced serum erythropoietin levels. Erythroid colonies from their blood samples could be grown without exogenous erythropoietin, and all such colonies were heterozygous for the mutation. The mutations included substitutions of leucine for lysine at position 539 of JAK2, which resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of bone marrow transplantation. The findings suggest that JAK2 exon 12 mutations define a distinct myeloproliferative syndrome that affects patients currently diagnosed with polycythemia vera or idiopathic erythrocytosis.