Program: Oral and Poster Abstracts
Session: 301. Platelet Activation and Biochemistry: Poster III
Analysis of human cord blood revealed that samples with TT risk SNP (R262W) in SH2B3/LNK was associated with expansion of hematopoietic stem cells (HSCs), increased MPL signaling in HSCs, increased megakaryopoiesis, and a paradoxical increased expression of LNK mRNA, indicating reduced LNK function but induction of LNK transcription downstream of increased MPL signaling. Since humans are hypercholesterolemic relative to mice, to assess the role of reduced LNK function in athero-thrombosis, we transplanted WT or Lnk-/- bone marrow (BM) cells into irradiated WT or low-density lipoprotein receptor knock-out (Ldlr-/-) recipient mice and fed the recipients with chow and western type diet (WTD), respectively. Although Lnk-/- BM recipients showed similarly increased platelet counts on both diets, we found that platelet activation and aggregation, formation of platelet/leukocyte aggregates, atherosclerosis and arterial thrombosis were markedly increased by the combination of hyperlipidemia and hematopoietic LNK deficiency. These diet-genotype interactions mirrored an increase in mean platelet volume, protease-activated receptor-4 (PAR4) agonist-induced P-selectin exposure on platelets and platelet protein kinase C (PKC) activity, suggesting increased platelet granule secretion. We also observed an increased number of bone marrow myeloid progenitor cells expressing elevated levels of the common-beta subunit (CBS) of the interleukin-3/granulocyte-macrophage colony-stimulating factor (IL-3/GM-CSF) receptor, which promotes leukocytosis and the formation of platelet/leukocyte aggregates in the bloodstream. The increased P-selectin exposure, platelet aggregation and PKC activity were largely reversed by high-
These studies suggest that SH2B3/LNK loss of function variants lead to HSC expansion, overproduction of platelets, and in the setting of hypercholesterolemia, markedly increased myeloid cells, platelet activation and formation of platelet/leukocyte aggregates, leading to accelerated atherosclerosis and arterial thrombosis. Our studies point to the importance of treating dyslipidemia in the setting of platelet and myeloid cell overproduction, as observed in subjects with SH2B3/LNK risk alleles.
Disclosures: Levine: Loxo Oncology: Membership on an entity’s Board of Directors or advisory committees ; CTI BioPharma: Membership on an entity’s Board of Directors or advisory committees ; Foundation Medicine: Consultancy . Tall: Amgen: Consultancy ; Arisaph: Consultancy ; CSL: Consultancy .
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