Characterization of murine JAK2V617F-positive myeloproliferative disease.
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.
Bumm
Thomas G P
TG
Center for Hematologic Malignancies, Oregon Health and Science University Cancer Institute, Portland, OR 97239, USA.
Elsea
Collin
C
Corbin
Amie S
AS
Loriaux
Marc
M
Sherbenou
Daniel
D
Wood
Lisa
L
Deininger
Jutta
J
Silver
Richard T
RT
Druker
Brian J
BJ
Deininger
Michael W N
MW
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D002460:Cell Line; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000097:blood; D005355:Fibrosis; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D006411:Hematopoiesis, Extramedullary; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D011086:Polycythemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011087:Polycythemia Vera / Q000209:etiology / Q000235:genetics / Q000473:pathology; D017467:Receptors, Erythropoietin / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D017467:Receptors, Erythropoietin; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2