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Mice expressing a JAK2 exon 12 mutation display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Grisouard, Jean and Romanet, Vincent and Murakami, Masato and Skoda, Radek and Radimerski, Thomas (2016) Mice expressing a JAK2 exon 12 mutation display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis. Blood, 2015-1 (2015-1). pp. 1-32. ISSN 27288519

Abstract

Mutations in JAK2 exon 12 are found in about half of 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 mutation in hematopoiesis showed strong increase in red blood cell parameters, but normal neutrophil and platelet counts, splenomegaly and reduced overall survival. Histopathology revealed increased erythropoiesis in bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were not altered compared to wildtype controls. Phosphorylation of Stat5 and Stat3 proteins was not significantly increased , but the expression of a Stat5 target gene, transferrin receptor-1 (Tfr1), was elevated in JAK2-N542-E543del mice. Furthermore, erythroferrone (Erfe) was increased and hepcidin (Hamp) was decreased. Similar changes in the expression of TFR1, ERFE and HAMP were also found in PV patients with JAK2 exon 12 mutations. We suggest that the strong phenotype in JAK2-N542-E543del mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells.

Item Type: Article
Date Deposited: 12 Aug 2016 00:45
Last Modified: 12 Aug 2016 00:45
URI: https://oak.novartis.com/id/eprint/28055

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