The JAK2 V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2 V617F , showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2 V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hema- IntroductionMyeloproliferative disorders are a group of conditions characterized by chronic increases in some or all of the blood cells (platelets, white blood cells, and red blood cells). [1][2][3] This group of blood disorders includes polycythemia vera (PV), essential (or primary) thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia (CML). PV is characterized by increased production of all 3 types of cells, whereas ET is manifest in the elevation of platelets. PMF is a disease in which fibrous (scar-like) tissues form in the marrow as a result of abnormal production of red cells, white cells, and platelets. CML is characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the peripheral blood. It is generally thought that MPDs arise from a transformation in a hematopoietic stem cell. Indeed, CML is now defined by its causative molecular lesion, the BCR-ABL fusion gene, which most commonly results from the Philadelphia translocation (Ph). Because of this defined molecular defect, a highly effective drug, namely, imatinib mesylate (Gleevec; Novartis, Basel, Switzerland), has been developed to treat CML. 4 So far, there is no effective cure for the 3 Ph-negative MPDs. Recently, 5 groups have identified a gain-of-function mutation of tyrosine kinase JAK2, which likely represents a major molecular defect in approximately 90% patients with PV and in approximately 50% of patients with ET or PMF. [5][6][7][8][9][10] The JAK2 mutant displays deregulated kinase activity and generates a PV-like phenotype in mouse bone marrow transplant models. [11][12][13][14] Studies also demonstrated infrequent occurrence of this mutation in chronic myelomonocytic leukemia, atypical myeloproliferative disorders, myelodysplastic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, and acute myeloid leukemia. [15][16][17][18][19] Interestingly, our recent studies also demonstrated that nearly 1% of blood samples collected fr...