title: LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Liana
authors.initials: L
authors.lastname: Tascau
authors.affiliation: 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.
authors.forename: Joanna
authors.initials: J
authors.lastname: Balcerek
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: 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.
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.affiliation: 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.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.affiliation: 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.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human
keywords: atherosclerosis; cholesterol; hematopoiesis; hypercholesterolemia; thrombosis