Wei Wang1, Yang Tang1, Ying Wang1, Liana Tascau1, Joanna Balcerek1, Wei Tong1, Ross L Levine1, Carrie Welch1, Alan R Tall1, Nan Wang2. 1. From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY. 2. From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY. nw30@columbia.edu.
Abstract
RATIONALE: Human genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3, which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood. OBJECTIVE: To understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis. METHODS AND RESULTS: Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and atherosclerosis, but only in the setting of hypercholesterolemia. Hypercholesterolemia acts synergistically with LNK deficiency to increase interleukin 3/granulocyte-macrophage colony-stimulating factor receptor signaling in bone marrow myeloid progenitors, whereas in platelets cholesterol loading combines with Lnk deficiency to increase activation. Platelet LNK deficiency increases myeloproliferative leukemia virus oncogene signaling and AKT activation, whereas cholesterol loading decreases SHIP-1 phosphorylation, acting convergently to increase AKT and platelet activation. Together with increased myelopoiesis, platelet activation promotes prothrombotic and proatherogenic platelet/leukocyte aggregate formation. CONCLUSIONS: LNK (R262W) is a loss-of-function variant that promotes thrombopoietin/myeloproliferative leukemia virus oncogene signaling and platelet and leukocyte production. In mice, LNK deficiency is associated with both increased platelet production and activation. Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with LNK deficiency.
RATIONALE: Human genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3, which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood. OBJECTIVE: To understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNKloss of function impacts atherosclerosis and thrombosis. METHODS AND RESULTS: Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and atherosclerosis, but only in the setting of hypercholesterolemia. Hypercholesterolemia acts synergistically with LNK deficiency to increase interleukin 3/granulocyte-macrophage colony-stimulating factor receptor signaling in bone marrow myeloid progenitors, whereas in platelets cholesterol loading combines with Lnk deficiency to increase activation. Platelet LNK deficiency increases myeloproliferative leukemia virus oncogene signaling and AKT activation, whereas cholesterol loading decreases SHIP-1 phosphorylation, acting convergently to increase AKT and platelet activation. Together with increased myelopoiesis, platelet activation promotes prothrombotic and proatherogenic platelet/leukocyte aggregate formation. CONCLUSIONS:LNK (R262W) is a loss-of-function variant that promotes thrombopoietin/myeloproliferative leukemia virus oncogene signaling and platelet and leukocyte production. In mice, LNK deficiency is associated with both increased platelet production and activation. Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with LNK deficiency.
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