Subject(s)
Calreticulin/genetics , Carcinogenesis/genetics , Gene Expression Regulation, Neoplastic , Hematologic Neoplasms/genetics , Myeloproliferative Disorders/genetics , Receptors, Thrombopoietin/genetics , Animals , Calreticulin/metabolism , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Line, Tumor , Cell Proliferation , Disease Models, Animal , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Humans , Mice , Mice, Inbred BALB C , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/mortality , Myeloproliferative Disorders/pathology , Precursor Cells, B-Lymphoid/metabolism , Precursor Cells, B-Lymphoid/pathology , Precursor Cells, B-Lymphoid/transplantation , Receptors, Thrombopoietin/metabolism , Retroviridae/genetics , Retroviridae/metabolism , Survival Analysis , Transduction, Genetic , Transgenes , Transplantation, HeterologousABSTRACT
Patients with myeloproliferative neoplasms (MPN) have high levels of inflammatory cytokines, some of which drive many of the debilitating constitutional symptoms associated with the disease and may also promote expansion of the neoplastic clone. We report here that monocytes from patients with MPN have defective negative regulation of Toll-like receptor (TLR) signaling that leads to unrestrained production of the inflammatory cytokine tumor necrosis factor α (TNF-α) after TLR activation. Specifically, monocytes of patients with MPN are insensitive to the anti-inflammatory cytokine interleukin 10 (IL-10) that negatively regulates TLR-induced TNF-α production. This inability to respond to IL-10 is a not a direct consequence of JAK2 V617F , as the phenotype of persistent TNF-α production is a feature of JAK2 V617F and wild-type monocytes alike from JAK2 V617F -positive patients. Moreover, persistent TNF-α production was also discovered in the unaffected identical twin of a patient with MPN, suggesting it could be an intrinsic feature of those predisposed to acquire MPN. This work implicates sustained TLR signaling as not only a contributor to the chronic inflammatory state of MPN patients but also a potential predisposition to acquire MPN.
Subject(s)
Myeloproliferative Disorders/metabolism , Signal Transduction , Toll-Like Receptors/metabolism , Tumor Necrosis Factor-alpha/metabolism , Alleles , Animals , Cytokines/metabolism , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Macrophages/metabolism , Mice , Monocytes/metabolism , Myeloproliferative Disorders/etiology , Protein Binding , Receptors, Interleukin-10/metabolism , Toll-Like Receptors/agonistsABSTRACT
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.
