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Abstract
Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2.
Highlights
The discovery of the somatic activating JAK2V617F mutation in the majority of patients with the chronic myeloproliferative neoplasms (MPNs) polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis marked a breakthrough in the understanding of the underlying molecular mechanism of these diseases [1,2,3,4]
These models included bone marrow transplantation experiments where JAK2V617F expression was driven by retroviral vectors [14, 16, 39, 40], or transgenic mice where JAK2V617F expression was either under the control of a tissue-specific or the endogenous promoter, respectively [19,20,21]
S3 Table), excluding a Myeloproliferative disease is reversible upon switching off JAK2V617F transgene expression reactive lesion
Summary
The discovery of the somatic activating JAK2V617F mutation in the majority of patients with the chronic myeloproliferative neoplasms (MPNs) polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis marked a breakthrough in the understanding of the underlying molecular mechanism of these diseases [1,2,3,4]. Transplantation of lethally irradiated mice with murine bone marrow cells transduced with a retrovirus expressing either JAK2V617F or MPLW515L was shown to result in pathological features that closely resemble human PV or myelofibrosis, respectively [14,15,16]. Disease hallmarks observed in the JAK2V617F mouse models include elevation of hemoglobin and hematocrit, leukocytosis, thrombocytosis, megakaryocyte hyperplasia, extramedullary hematopoiesis resulting in splenomegaly, and increased reticulin fibers in the bone marrow of some of the models
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