Blood (BLOOD )

Publisher: American Society of Hematology, American Society of Hematology

Description

Blood, The Journal of The American Society of Hematology is published 25 times (in two volumes) per year by The American Society of Hematology (ASH).

  • Impact factor
    9.78
    Show impact factor history
     
    Impact factor
  • 5-year impact
    9.34
  • Cited half-life
    6.70
  • Immediacy index
    2.11
  • Eigenfactor
    0.40
  • Article influence
    3.43
  • Website
    Blood website
  • Other titles
    Blood
  • ISSN
    0006-4971
  • OCLC
    1536582
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

American Society of Hematology

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • Cannot archive until publication
    • On author's personal website and departmental website
    • Must link to publisher version
    • NIH Authors articles will be automatically submitted to PubMed Central after 12 months
  • Classification
    ​ blue

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Hamza Celik1, Cates Mallaney2, Alok Kothari3, Elizabeth L. Ostrander1, Elizabeth Eultgen1, Andrew Martens1, Christopher A. Miller4, Jasreet Hundal4, Jeffery M. Klco5, and Grant A. Challen1,* 1 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States; 2 Division of Human and Statistical Genetics, Washington University School of Medicine, St. Louis, MO, United States; 3 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States; 4 The Genome Institute, Washington University School of Medicine, St. Louis, MO, United States; 5 Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States ↵* Corresponding author; email: gchallen{at}dom.wustl.edu Key points Dnmt3a-null HSCs cannot sustain long-term hematopoiesis.Co-operating c-Kit mutations drive leukemic transformation of Dnmt3a-null HSCs. AbstractGenome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A. We have recently shown that Dnmt3a is essential for hematopoietic stem cell differentiation. Here we investigated the effect of loss of Dnmt3a on hematopoietic transformation by forcing the normally quiescent HSCs to divide in vivo. Mice transplanted with Dnmt3a-null bone marrow in the absence of wild-type support cells succumbed to bone marrow failure (median survival 328 days) characteristic of myelodysplastic syndromes with symptoms including anemia, neutropenia, bone marrow hypercellularity and splenomegaly with myeloid infiltration. 2/25 mice developed myeloid leukemia with >20% blasts in the blood and bone marrow. 4/25 primary mice succumbed to myeloproliferative disorders, some of which progressed to secondary leukemia after long latency. Exome sequencing identified co-operating c-Kit mutations found only in the leukemic samples. Ectopic introduction of c-Kit variants into a Dnmt3a-deficient background produced acute leukemia with a short latency (median survival 67 days). Our data highlight crucial roles of Dnmt3a in normal and malignant hematopoiesis, and suggest that a major role for this enzyme is to facilitate developmental progression of progenitor cells at multiple decision checkpoints.Submitted August 7, 2014.Accepted September 25, 2014.Copyright © 2014 American Society of Hematology
    Blood 11/2014;
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    ABSTRACT: DNA METHYLTRANSFERASE 3A (DNMT3A) is mutated in hematological malignancies affecting myeloid, mixed, and lymphoid lineages and is associated with poor prognosis. Past studies in mice revealed Dnmt3a-KO HSCs had increased self-renewal, but no leukemia was observed. Here, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within one year. Animals were diagnosed with a spectrum of malignancies similar to those seen in patients with DNMT3A mutations, including myelodysplastic syndrome, acute myeloid leukemia, primary myelofibrosis, and T- and B-cell ALL. In some cases, acquired malignancies exhibited secondary mutations similar to those identified in patients. Loss of Dnmt3a led to disturbed methylation patterns that were distinct in lymphoid and myeloid disease, suggesting lineage-specific methylation aberrations promoted by Dnmt3a loss. Global hypomethylation was observed in all of the malignancies but lymphoid malignancies also exhibited hypermethylation particularly at promoter regions. This mouse model underscores the important role of Dnmt3a in normal hematopoietic development, and demonstrates that Dnmt3a loss-of-function confers a preleukemic phenotype on murine HSCs. This model may serve as a tool to study DNMT3A mutation-associated malignancies and for developing targeted strategies for eliminating preleukemic cells for prevention and treatment of hematological malignancies in the future. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
  • Blood 11/2014; 124(22):3180-1.
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    ABSTRACT: Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPPII) abolishing protein expression. TPPII is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPPII deficient mice, patient cells showed increased MHC I expression and most CD8+ T-cells had a senescent CCR7-CD127-CD28-CD57+ phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and IFN-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21- CD11c+ phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2 deficient fibroblasts. Telomere length was normal in patient fibroblasts and granulocytes and low normal in lymphocytes, compatible with activation of stress-induced rather than replicative senescence programs. TPPII deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
  • Blood 11/2014; 124(22):3330-2.
  • Blood 11/2014; 124(22):3178-9.
  • Blood 11/2014; 124(22):3179-80.
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    ABSTRACT: Immunotherapy of B-cell malignancies using CD19-targeted chimeric antigen receptor (CAR)-transduced T-cells or CD20-targeted therapeutic monoclonal antibodies has shown clinical efficacy. However, refractory disease and the emergence of antigen-loss tumor escape variants after treatment demonstrate the need to target additional antigens. Here, we aimed to target the B-cell receptor associated protein CD79b by a T-cell receptor (TCR)-based approach. Since thymic selection depletes high-avidity T-cells recognizing CD79b-derived peptides presented in self-HLA molecules, we aimed to isolate T-cells recognizing these peptides presented in allogeneic HLA. Peptide-HLA tetramers composed of CD79b peptides bound to either HLA-A2 or HLA-B7 were used to isolate T-cell clones from HLA-A*0201 and B*0702-negative individuals. For three distinct T-cell clones CD79b specificity was confirmed through CD79b gene transduction and CD79b-specific shRNA knockdown. The CD79b specific T cell clones were highly reactive against CD79b-expressing primary B-cell malignancies whereas no recognition of non-hematopoietic cells was observed. Although lacking CD79b cell surface expression, intermediate reactivity towards monocytes, hematopoietic progenitor cells and T-cells was observed. Quantitative RT-PCR revealed low CD79b gene expression in these cell types. Therefore, aberrant gene expression must be taken into consideration when selecting common, apparently lineage-specific self-antigens as targets for TCR-based immunotherapies. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Many patients with syndromes of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, have been reported to have a drug-induced etiology, and many different drugs have been suspected as a cause of TMA. We established criteria to assess the strength of evidence for a causal association of a drug with TMA and systematically searched for all published reports of drug-induced TMA (DITMA). We identified 1569 articles; 604 were retrieved for review; 344 reported evaluable data for 586 individual patients; 43 reported evaluable data on 46 patient groups. Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA. These criteria and data can provide support for clinicians evaluating patients with suspected TMA. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
  • Blood 11/2014; 124(22):3332-4.
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    ABSTRACT: Plasmodium vivax merozoites only invade reticulocytes, a minor though heterogeneous population of red blood cell precursors that can be graded by levels of transferrin receptor (CD71) expression. The development of a protocol that allows sorting reticulocytes into defined developmental stages and a robust ex vivo P. vivax invasion assay, has made it possible for the first time to investigate the fine scale invasion preference of P. vivax merozoites. Surprisingly, it was the immature reticulocytes (CD71(+)) that are generally restricted to the bone marrow that were preferentially invaded, whereas older reticulocytes (CD71(-)) principally found in the peripheral blood were rarely invaded. Invasion assays based on the CD71(+) reticulocyte fraction revealed substantial post-invasion modification. Thus, 3-6 hours after invasion the initially biomechanically rigid CD71(+) reticulocytes convert into a highly deformable CD71(-) infected red blood cell devoid of host reticular matter, a process that normally spans 24 hours for uninfected reticulocytes. Concurrent with these changes, clathrin pits disappear by 3 hours post-invasion, replaced by distinctive caveolae nanostructures. These two hitherto unsuspected features of P. vivax invasion, a narrow preference for immature reticulocytes and a rapid remodelling of the host cell, provide important insights pertinent to the pathobiology of the P. vivax infection. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Following injury, platelets rapidly interact with the exposed extracellular matrix (ECM) of the vessel wall and the surrounding tissues. Hyaluronan (HA) is a major glycosaminoglycan component of the ECM and plays a significant role in regulating inflammation. We have recently reported that human platelets degrade HA from the surfaces of activated endothelial cells into fragments capable of inducing immune responses by monocytes. We also showed that human platelets contain the enzyme hyaluronidse-2 (HYAL2), one of two major hyaluronidases that digest HA in somatic tissues. The deposition of HA increases in the inflamed tissues in several inflammatory diseases, including Inflammatory Bowel Disease (IBD). We therefore wanted to define the mechanism by which platelets degrade HA in the inflamed tissues. In this study, we show that human platelets degrade the pro-inflammatory matrix HA through the activity of HYAL2 and that platelet activation causes the immediate translocation of HYAL2 from a distinct population of α-granules to platelet surfaces, where it exerts its catalytic activity. Finally, we show evidence that patients with IBD have lower platelet HYAL2 levels and activity than healthy controls. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: A macrophage engulfs another cell or foreign particle in an adhesive process that often activates Myosin-II, unless the macrophage also engages 'Marker of Self' CD47 that inhibits Myosin. For many cell types, adhesion-induced activation of Myosin-II is maximized by adhesion to a rigid rather than a flexible substrate. Here we demonstrate that rigidity of a phagocytosed cell also hyperactivates Myosin-II, which locally overwhelms 'Self' signaling at a phagocytic synapse. Cell stiffness is one among many factors including shape that can change in senescence and in diseases ranging from inherited anemias and malaria to cancer. Controlled stiffening of normal human RBCs in different shapes does not compromise CD47's interaction with the macrophage 'Self'-recognition receptor, SIRPA. Uptake of antibody-opsonized RBCs is always fastest with rigid RBC-Discocytes that also show maximal active Myosin-II at the synapse can dominate 'Self' signaling by CD47. Rigid but rounded RBC-Stomatocytes signal 'Self' better than rigid RBC-Discocytes, highlighting the effects of shape on CD47 inhibition. Physical properties of phagocytic targets thus regulate 'Self' signaling, as is relevant to clearance of rigid RBCs after blood storage, clearance of rigid pathological cells such as thalassemic or sickle cells, and even to interactions of soft/stiff cancer cells with macrophages. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Bone marrow megakaryocytes produce platelets by extending long cytoplasmic protrusions, designated proplatelets, into sinusoidal blood vessels. While microtubules are known to regulate platelet production, the underlying mechanism of proplatelet elongation has yet to be resolved. Here we report that proplatelet formation is a process that can be divided into repetitive phases - extension, pause and retraction - as revealed by differential interference contrast and fluorescence loss after photoconversion time-lapse microscopy. Furthermore we show that microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein under static and physiological shear stress by using fluorescence recovery after photobleaching in proplatelets with fluorescence tagged β1-tubulin. A refined understanding of the specific mechanisms regulating platelet production will yield strategies to treat patients with thrombocythemia or thrombocytopenia. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mTOR signaling and phosphorylation of ULK1 in mtDNA-mutator mice resulted in proteasome-mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wild-type and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathologic feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPC). Most patients respond to immunosuppressive therapies (IST), but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of clonal evolution to -7. All patients had a dominant HSPC clone bearing specific acquired mutations detected in 50 to 90 percent of circulating granulocytes. However, mutations in candidate genes associated with MDS/AML were present in only four cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition prior to the emergence of -7. Single telomere length analysis (STELA) confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML following SAA, and provides a possible mechanism for development of aneuploidy. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Intron-22-inversion (I22I)-patients express the entire FVIII-amino-acid sequence intracellularly as two non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM-status". Mutations conferring a positive I-FVIII-CRM-status are associated with low inhibitor-risk and are "pharmacogenetically-relevant" because inhibitor-risk may be affected by the: nature of the therapeutic-FVIII-protein (tFVIII); affinity of any tFVIII-derived-foreign peptide (tFVIII-fp) for any HLA-class-II isomer (HLA-II) comprising individual-MHC-repertoires; and stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely- or substantially-negative I-FVIII-CRM-status are "pharmacogenetically-irrelevant" because inhibitor-risk is high with any tFVIII and individual-MHC-repertoire. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a bone marrow cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13 and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs) as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Repeated therapeutic plasma exchange (TPE) has been advocated to remove heparin-induced thrombocytopenia (HIT) IgG antibodies prior to cardiac/vascular surgery in patients who have serologically-confirmed acute or subacute HIT; for this situation, a negative platelet activation assay (e.g., platelet serotonin-release assay [SRA]) has been recommended as the target serological endpoint to permit safe surgery. We compared reactivities in the SRA and an anti-PF4/heparin IgG-specific enzyme-immunoassay (EIA), testing serial serum samples in a patient with recent (subacute) HIT who underwent serial TPE pre-cardiac surgery, as well as for 15 other serially-diluted HIT sera. We observed that post-TPE/diluted HIT sera-when first testing SRA-negative-continue to test strongly positive by EIA-IgG. This dissociation between the platelet activation assay and a PF4-dependent immunoassay for HIT antibodies indicates that patients with subacute HIT undergoing repeated TPE prior to heparin re-exposure should be tested by serial platelet activation assays even when their EIAs remain strongly positive. Copyright © 2014 American Society of Hematology.
    Blood 11/2014;
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    ABSTRACT: Recently it has become apparent that superficial vein thrombosis (SVT) can have serious complications. However, the magnitude of the risk of subsequent deep venous and arterial thrombotic events remains unknown. We examined this in a nationwide population-based setting during a period when SVT was not treated routinely with anticoagulants. The Danish National Registry of Patients, covering all Danish hospitals, was used to identify 10,973 patients with a first-time diagnosis of SVT during 1980-2012. A comparison cohort of 515,067 subjects, matched on age, sex and calendar year, was selected from the general Danish population. Outcomes were venous thromboembolism (VTE), acute myocardial infarction (AMI), ischaemic stroke, and death. During median follow-up of 7 years, the incidence rate of VTE was 18.0/1000 person-years (95% confidence interval (CI) 17.2-18.9). The highest risk occurred in the first 3 months (3.4%; 95%CI 3.0-3.7). Compared with the general population, the hazard ratio (HR) was 71.4 (95%CI 60.2-84.7) in this period, steadily decreasing to 5.1 (95%CI 4.6-5.5), 5 years after the SVT. HRs for AMI, stroke and death were 1.2 (95%CI 1.1-1.3), 1.3 (95%CI 1.2-1.4) and 1.3 (95%CI 1.2-1.3) respectively, with the highest risk also shortly after SVT. These data indicate the prognostic importance of SVT and may form the basis for clinical decision-making regarding anticoagulation.
    Blood 11/2014;