JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis.
Mutations in JAK2 exon 12 are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617F mutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del, the most frequent JAK2 exon 12 mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12) showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12 mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12 mice showed decreased expression of hepcidin and increased expression of transferrin receptor-1 and erythroferrone, suggesting that the strong erythroid phenotype in Ex12 mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells.
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Jean
J
Grisouard
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Sai
S
Li
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Lucia
L
Kubovcakova
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Tata Nageswara
TN
Rao
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Sara C
SC
Meyer
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Pontus
P
Lundberg
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Hui
H
Hao-Shen
Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
Vincent
V
Romanet
Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
Masato
M
Murakami
Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland; and.
Thomas
T
Radimerski
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Stephan
S
Dirnhofer
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
Radek C
RC
Skoda
D000818:Animals; D001483:Base Sequence; D004912:Erythrocytes / Q000473:pathology; D004920:Erythropoiesis; D005091:Exons; D007501:Iron / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D007501:Iron; C507924:JAK2 protein, human; D053614:Janus Kinase 2