JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis

Abstract

A JAK2 V617F 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 V617F in recipient irradiated mice. Hosts were analyzed during the 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 to 4 months, polycythemia regressed, abnormally shaped red blood cells and platelets were seen in circulation, and a deposition of reticulin fibers 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 toward myelofibrosis. This work demonstrates that JAK2 V617F is sufficient for polycythemia and fibrosis development and offers an in vivo model to assess novel therapeutic approaches for JAK2 V617F

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

“…The discovery of a somatic mutation (V617F) in the tyrosine kinase, Janus Kinase 2 (JAK2) [1][2][3][4][5], was the most important advance in MPN since the discoveries 30 years ago that hematopoiesis in these disorders was both autonomous and clonal [6][7][8]. Although the murine models have provided unequivocal evidence that JAK2 V617F is able to cause MPNs, there is significant heterogeneity in disease phenotypes between different murine lines and even within the same line, suggesting that disease phenotype is affected by other unknown genetic or epigenetic factors [2,[9][10][11][12]. In particular, PV is characterized by raised red cell mass and sometimes increased platelet and white cell counts, while ET is defined by an elevated platelet count alone and a normal red cell mass.…”

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

“…In murine bone marrow transfer models, introduction of the Jak2-V617F mutation is sufficient to induce a PV phenotype (Bumm et al, 2006;Lacout et al, 2006;Wernig et al, 2006;Zaleskas et al, 2006). Thus, the Jak2-V617F mutation seems to be very critical for disease development, but the evolution of the human disease and involvement of other factors is not fully understood.…”

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

“…Similarly, the recently described point mutation in the JAK2 kinase (JAK2 V617F ), is present in only around 50% of ET patients [9,10]. Because introduction of the JAK2 V617F mutation into a murine bone marrow transplantation model recapitulates many features of myeloproliferative disorders, including, in some cases, thrombocythemia, it appears intimately involved in the molecular etiology of disease development [11,12]. This observation raises the obvious question, which molecular alterations underlie the etiology of non-JAK2 V617F carrying ET.…”