Abstract
The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.
Highlights
The myeloproliferative disorders (MPD) are a heterogeneous group of disorders characterized by expansion of one or more of the myeloid lineages
No difference was observed in the absence of IL-3, indicating that JAK2V617F induces cytokine hypersensitivity but not complete cytokine independence, consistent with the observation that primary polycythemia vera (PV) progenitor cells are hypersensitive to cytokines but not cytokine independent [15]
We found no differences in serum levels of IL-2, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF) between JAK2WT and JAK2V617F mice, whereas average serum levels of granulocyte colonystimulating factor (G-CSF) were significantly lower (99 pg/mL compared with 343 pg/mL; P = 0.037) in JAK2V617F mice compared with JAK2WT mice (Fig. 5D)
Summary
The myeloproliferative disorders (MPD) are a heterogeneous group of disorders characterized by expansion of one or more of the myeloid lineages. A mutation (V617F) in the pseudokinase (JH2) domain of the Janus-activated kinase (JAK) 2 tyrosine kinase has been identified in 65% to 97% of patients with PV, 35% to 95% of patients with IMF, and 23% to 43% of patients with ET [5,6,7,8]. JAK2 is involved in signaling downstream of many cytokine receptors, including the erythropoietin (Epo) receptor (EpoR), thrombopoietin receptor, and granulocyte macrophage colony-stimulating factor (GM-CSF) receptors. Consistent with this function, JAK2À/À embryos die from profound anemia around days 11 to 13 of embryogenesis [13, 14]. We provide a detailed characterization of JAK2V617F-positive murine MPD
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