JAK2 expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis Short title: MPD induced in mice by JAK2 expression

A JAK2 mutation is frequently found in several BCR/ABL-negative myeloproliferative disorders. To address the contribution of this mutant to the pathogenesis of these different myeloproliferative disorders, we used an adoptive transfer of marrow cells transduced with a retrovirus expressing JAK2 in recipient irradiated mice. Hosts were analyzed during 6 months after transplantation. For a period of 3 months, mice developed polycythemia, macrocytosis and usually peripheral blood granulocytosis. Transient thrombocytosis was only observed in a low expresser group. All mice displayed trilineage hyperplasia in marrow and spleen along with an amplification of myeloid and erythroid progenitor cells and a formation of endogenous erythroid colonies. After 3-4 months, polycythemia regressed, abnormally shaped red blood cells and platelets were seen in circulation and a deposition of reticulin fibers and collagen was observed in marrow and spleen. Development of fibrosis was associated with anemia, thrombocytopenia, high neutrophilia and massive splenomegaly. These features mimic human Polycythemia Vera and its evolution towards myelofibrosis. This work demonstrates that JAK2 is sufficient for polycythemia and fibrosis development and offers an in vivo model to assess novel therapeutic approaches for JAK2-positive pathologies. Questions remain regarding the exact contribution of JAK2 in other myeloproliferative disorders. For personal use only. on November 12, 2017. by guest www.bloodjournal.org From