Expression of V617F JAK2 in Mice Leads to MPD Mimicking Human ET, Idiopahtic Myelofibrosis, and PV.

An acquired JAK2 V617F mutation has been detected in up to 90% of patients with polycythemia vera (PV) and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). However, how a single mutation may be responsible for such different clinical phenotypes is unknown. Mice transplanted with bone marrow cells in which V617F JAK2 was retrovirally expressed developed PV-like features, but not ET or IMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated transgenic mice expressing V617F JAK2 driven by the murine H2Kb promoter. We established two lines. The expression of V617F JAK2 mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines. One line showed leukocytosis after 4 months of age, with a predominance of granulocytes. Among 43 mice, examined after 3 months of age, 8 (19%) showed polycythemia and 14 (33%) showed thrombocythemia. Two polycythemia cases also showed thromobocytosis. The other line showed extreme leukocytosis and thromobocytosis at one month of age. The leukocytosis progressed as the animals aged, but the thrombocytosis tended to resolve at 8 months. They showed anemia that means Hb value from 9 to 10 g/dL at one month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly with myeloid cell and megakaryocyte invasion was observed. We conclude that in vivo expression of V617F JAK2 results in ET-like, IMF-like, and PV-like disease.