JAK2V617I results in cytokine hypersensitivity without causing an overt myeloproliferative disorder in a mouse transduction-transplantation model

A germline JAK2V617I point mutation results in hereditary thrombocytosis and shares some phenotypic features with myeloproliferative neoplasm, a hematologic malignancy associated with a somatically acquired JAK2V617F mutation. We established a mouse transduction-transplantation model of JAK2V617I that recapitulated the phenotype of humans with germline JAK2V617I. We directly compared the phenotypes of JAK2V617I and JAK2V617F mice. The JAK2V617I mice had increased marrow cellularity with expanded myeloid progenitor and megakaryocyte populations, but this phenotype was less severe than that of JAK2V617F mice. JAK2V617I resulted in cytokine hyperresponsiveness without constitutive activation in the absence of ligand, whereas JAK2V617F resulted in constitutive activation. This may explain why JAK2V617I produces a mild myeloproliferative phenotype in the mouse model, as well as in humans with germline JAK2V617I mutations.