Characterization of murine JAK2V617F-positive myeloproliferative disease

Thomas G.P. Bumm, Collin Elsea, Amie S. Corbin, Marc Loriaux, Daniel Sherbenou, Lisa Wood, Jutta Deininger, Richard T. Silver, Brian J. Druker, Michael W.N. Deininger

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154 Scopus citations

Abstract

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 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-α was increased, possibly exerting a negative effect on JAK2V617F7-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.

Original languageEnglish (US)
Pages (from-to)11156-11165
Number of pages10
JournalCancer Research
Volume66
Issue number23
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bumm, T. G. P., Elsea, C., Corbin, A. S., Loriaux, M., Sherbenou, D., Wood, L., Deininger, J., Silver, R. T., Druker, B. J., & Deininger, M. W. N. (2006). Characterization of murine JAK2V617F-positive myeloproliferative disease. Cancer Research, 66(23), 11156-11165. https://doi.org/10.1158/0008-5472.CAN-06-2210