Blood
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Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormone-evoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. ⋯ To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploinsufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A-Slp4-a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature.
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Platelets play crucial functions in hemostasis and the prevention of bleeding. During H1N1 influenza A virus infection, platelets display activation markers. The platelet activation triggers during H1N1 infection remain elusive. ⋯ Using a combination of in vitro and in vivo approaches, we found that the antibodies from H3N2-immunized mice activate transgenic mouse platelets that express FcγRIIA when put in the presence of H1N1, suggesting that cross-reacting influenza antibodies suffice. Alternatively, H1N1 can activate platelets via thrombin formation, independently of complement and FcγRIIA. These observations identify both the adaptive immune response and the innate response against pathogens as 2 intertwined processes that activate platelets during influenza infections.
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Whole genome sequencing has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 in Waldenström macroglobulinemia (WM). CXCR4 somatic mutations in WM are the first ever reported in human cancer and are similar to nonsense (NS) and frameshift (FS) germline mutations found in warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome. We genotyped lymphoplasmacytic cells from 175 WM patients and observed significantly higher bone marrow (BM) disease involvement, serum immunoglobulin-M levels, and symptomatic disease requiring therapy, including hyperviscosity syndrome in those patients with MYD88(L265P)CXCR4(WHIM/NS) mutations (P < .03). ⋯ Unexpectedly, risk of death was not impacted by CXCR4 mutation status, but by MYD88(WT) status (hazard ratio 10.54; 95% confidence interval 2.4-46.2, P = .0018). Somatic mutations in MYD88 and CXCR4 are important determinants of clinical presentation and impact overall survival in WM. Targeted therapies directed against MYD88 and/or CXCR4 signaling may provide a personalized treatment approach to WM.
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In this issue of Blood, Treon and colleagues provide strong evidence that mutations in MYD88 and CXCR4 dictate clinical presentation and survival in Waldenström macroglobulinemia (WM).