Dr. Bob Löwenberg (Editor-in-Chief) and Dr. Nancy Berliner (Deputy Editor-in-Chief) have combined efforts to identify some of the most outstanding Blood articles that have appeared either in print or online during the two-month interval between issues of The Hematologist. The citations are annotated to provide readers both with a concise description of the thrust of the article and an explanation of why the paper is particularly important. The goal is to underscore the remarkable research that is published in Blood and to highlight the exciting progress that is being made in the field.
APRIL 18, 2013
Newman DK. CD39 Target Practice. Blood. 2013;121:3061-3062.
Hohmann JD, Wang X, Krajewski S, et al. Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Blood. 2013;121:3067-3075.
The NTPDase CD39 (a dense granule constituent), degrades the primary platelet activating/recruiting molecule ADP, and as such, represents a promising target for antithrombotic therapy. In this Plenary paper, Hohmann and colleagues examine the effects of targeting of CD39 to a developing clot. Their strategy involved creating a chimeric protein consisting of CD39 fused to a single-chain antibody specific for glycoprotein IIb/IIIa. The investigators report that binding of this construct (called targ-CD39) to activated platelets impeded the perpetuation phase of thrombus formation, thereby retarding growth of the clot without interfering with formation of the initial sealing layer of platelets. Thus, the targ-CD39 construct is a novel antithrombotic agent as it retards clot growth while allowing for adequate hemostasis.
APRIL 11, 2013
Bakchoul T, Zöllner H, Amiral J, et al. Anti-protamine–heparin antibodies: incidence, clinical relevance and pathogenesis. Blood. 2013;121:2821-2827.
Lee GM, Welsby IJ, Bute BP, et al. High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood. 2013;121:2828-2835.
Two manuscripts report the unexpected finding that a significant proportion of patients undergoing cardiopulmonary bypass develop antibodies against protamine. In the first study, Bakchoul et al. report that nearly 10 percent of patients had anti-protamine antibodies at baseline, increasing to nearly 27 percent within 10 days of bypass. Lee et al. report similar findings: 29 percent of post-bypass patients developed antibodies within 30 days. Antibodies were more common in patients with diabetes, and protamine-heparin complexes cross-reacted with protamine-containing insulin preparations. In most patients, these antibodies were clinically silent and declined in titer over several months; however, in a small number of patients, the antibodies bound and activated platelets in the presence of protamine. This process may be a rare cause of unexplained thrombocytopenia and thrombosis, sharing clinical and pathophysiologic features with heparin-induced thrombocytopenia.
MARCH 28, 2013
Drewniak AA, Gazendam RP, Tool ATJ, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121:2385-2392.
This Plenary paper reports on the mechanism of invasive fungal infections in individuals with Caspase recruitment domain-containing protein 9 (CARD9) deficiency. Candida fungal infections can be either mucosal or systemic, and the pathways that protect against the two types of infection are distinct. Mucosal candida is controlled by IL-17 producing lymphocytes (Th17 lymphocytes) that are components of the adaptive immune system, while prevention of systemic candidiasis is mediated by neutrophils that are constituents of innate immunity. Drewniak and colleagues report that a patient with CARD9 deficiency suffering from Candida dubliniensis meningoencephalitis had both a selective neutrophil killing defect and a subnormal number of Th17 lymphocytes. These studies, which indicate a role for CARD9 in both Th17 development and neutrophil function, suggest that this pleotropic protein sits at the intersection of the two pathways of immunity.
MARCH 21, 2013
Vegliante MC, Palomero J, Perez-Galan P, et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood. 2013;121:2175-2185.
While the neural transcription factor SOX11 is a commonly upregulated gene in mantle cell lymphoma but not in other mature B-cell lymphomas, its role in the pathogenesis of the disease has remained largely obscure. In this paper, Vegliante and colleagues report the results of studies designed to delineate the oncogenic and mechanistic effects of SOX11. The investigators analyzed the genes and transcriptional programs controlled by SOX11, integrating genomic and biologic approaches and demonstrating effects on plasma cell differentiation. The findings represent a conceptual advance in our understanding of the pathobiology of this aggressive form of malignant lymphoma.
MARCH 15, 2013
Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, IgM monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific PCR. Blood. 2013;121:2051-2058.
In this study, researchers report on a recurrent mutation in the MYD88 gene detected in more than 90 percent of patients with Waldenström macroglobulinemia. Additionally, allele-specific polymerase chain reaction detected the same mutation in more than half of patients with IgM MGUS (monoclonal gammopathy of undetermined significance), but not in patients with other forms of multiple myeloma, chronic lymphocytic leukemia, or splenic lymphoma. These findings suggest that MYD88 mutation may be an early cancer-causing event in a specific subset of lymphoproliferative diseases characterized by clonal expansion of IgM-producing lymphoplasmactyic cells.
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