UC Irvine

A germline JAK2(V617I) point mutation results in hereditary thrombocytosis and shares some phenotypic features with myeloproliferative neoplasm, a hematologic malignancy associated with a somatically acquired JAK2(V617F) mutation. We established a mouse transduction-transplantation model of JAK2(V617I) that recapitulated the phenotype of humans with germline JAK2(V617I). We directly compared the phenotypes of JAK2(V617I) and JAK2(V617F) mice. The JAK2(V617I) mice had increased marrow cellularity with expanded myeloid progenitor and megakaryocyte populations, but this phenotype was less severe than that of JAK2(V617F) mice. JAK2(V617I) resulted in cytokine hyperresponsiveness without constitutive activation in the absence of ligand, whereas JAK2(V617F) resulted in constitutive activation. This may explain why JAK2(V617I) produces a mild myeloproliferative phenotype in the mouse model, as well as in humans with germline JAK2(V617I) mutations.