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Cancer Research 66, 11156, December 1, 2006. doi: 10.1158/0008-5472.CAN-06-2210
© 2006 American Association for Cancer Research
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Molecular Biology, Pathobiology, and Genetics

Characterization of Murine JAK2V617F-Positive Myeloproliferative Disease

Thomas G.P. Bumm1, Collin Elsea1,3, Amie S. Corbin1,4, Marc Loriaux1,2, Daniel Sherbenou1, Lisa Wood1,3, Jutta Deininger2, Richard T. Silver5, Brian J. Druker1,4 and Michael W.N. Deininger1

1 Center for Hematologic Malignancies, Oregon Health and Science University Cancer Institute; 2 Department of Pathology, Oregon Health and Science University; 3 Oregon Health and Science University School of Nursing; 4 Howard Hughes Medical Institute, Portland, Oregon; and 5 Cornell University, New York, New York

Requests for reprints: Michael W.N. Deininger, Oregon Health and Science University Cancer Institute L592, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-1603; Fax: 503-494-3688; E-mail: deininge{at}ohsu.edu.

The JAK2V617F 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 JAK2V617F-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 JAK2V617F-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2V617F 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 JAK2V617F mice, suggesting that the mutation may not confer self-renewal capacity. (Cancer Res 2006; 66(23): 11156-65)




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2006 by the American Association for Cancer Research.