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    Lowexpression confers redox hypersensitivity and identifies an indolent clinical behavior in CLL.
    Blood 2018 Feb 21. Epub 2018 Feb 21.
    Research Center LURM (Interdepartmental Laboratory of Medical Research), University of Verona, Verona, Italy;
    B-cell receptor (BCR) signaling is a key determinant of variable clinical behavior and a target for therapeutic interventions in chronic lymphocytic leukemia (CLL). Endogenously produced HOis thought to fine-tune the BCR signaling by reversibly inhibiting phosphatases. However, little is known about how CLL cells sense and respond to such redox cues and what impact they have on CLL. Read More

    The search for new antithrombotic mechanisms and therapies that may spare hemostasis.
    Blood 2018 Feb 21. Epub 2018 Feb 21.
    Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, United States
    Current antithrombotic drugs, including widely used antiplatelet agents and anticoagulants, are associated with significant bleeding risk, which increases morbidity and mortality. Nevertheless, there is emerging experimental evidence that suggests that the molecular and cellular mechanisms of hemostasis and thrombosis can be separated, thereby raising the possibility of new antithrombotic therapeutic targets with reduced bleeding risk. We summarize some recently emerging examples of agents with antithrombotic activities that seem to spare hemostasis. Read More

    Somatic IL4R Mutations in Primary Mediastinal Large B-cell lymphoma lead to constitutive JAK-STAT signaling activation.
    Blood 2018 Feb 21. Epub 2018 Feb 21.
    Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, Canada;
    Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of diffuse large B cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somaticmutations in 15 out of 62 primary cases of PMBCL (24. Read More

    Glutaminolysis is a metabolic dependency in FLT3acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.
    Blood 2018 Feb 20. Epub 2018 Feb 20.
    Wellcome Trust-MRC Cambridge Stem Cell Institute, United Kingdom;
    FLT3 internal tandem duplication (FLT3) are common mutations in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3AML patients remains poor and demands the identification of novel, specific and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide CRISPR/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Read More

    First-in-human Phase 1 Clinical Study of the IL-15 Superagonist Complex ALT-803 to Treat Relapse after Transplantation.
    Blood 2018 Feb 20. Epub 2018 Feb 20.
    Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, United States;
    New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin (IL)-15 is a cytokine that stimulates CD8T cell and NK cell anti-tumor responses, and we hypothesized this cytokine may augment anti-leukemia/lymphoma immunity in vivo. To test this, we performed a first-in-human multi-center phase 1 trial (ClinicalTrials. Read More

    mTOR masters monocyte development in bone marrow by decreasing the inhibition of STAT5 on IRF8.
    Blood 2018 Feb 20. Epub 2018 Feb 20.
    State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;
    Monocytes and macrophages play a key role in defending pathogens, removing the dead cells or cell debris and wound healing. mTOR inhibitor, rapamycin (RPM) is widely used in clinics to treat patients with organ transplantation or tumors. The role of mTOR in monocyte/macrophage development remains to be clarified. Read More

    Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset.
    Blood 2018 Feb 20. Epub 2018 Feb 20.
    Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University (ALU) Freiburg, Germany
    Conditioning-induced damage of the intestinal tract plays a critical role during the onset of acute graft-versus-host disease (GVHD). Therapeutic interference with these early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T-cells. However not donor T-cells but neutrophils reach the sites of tissue injury first and therefore could be a potential target for GVHD-prevention. Read More

    LSD1 inhibition exerts its anti-leukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML.
    Blood 2018 Feb 16. Epub 2018 Feb 16.
    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;
    Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML. Read More

    Mouse and human HSPC immobilization in liquid culture by CD43 or CD44-antibody coating.
    Blood 2018 Feb 16. Epub 2018 Feb 16.
    Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland;
    Keeping track of individual cell identifications is imperative to the study of dynamic single cell behavior over time. Highly motile hematopoietic stem and progenitor cells (HSPCs) migrate quickly and do not adhere, and thus must be imaged very frequently to keep cell identifications. Even worse, they are also flushed away during medium exchange. Read More

    Immune evasion via PD-1/PD-L1 on NK-cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL.
    Blood 2018 Feb 15. Epub 2018 Feb 15.
    Diamantina Institute, University of Queensland, Brisbane, QLD, Australia;
    Much focus has been on the interaction of PD-L1 on malignant B-cells with PD-1 on effector T-cells in inhibiting anti-lymphoma immunity. We sought to establish the contribution of NK-cells and inhibitory CD163monocytes/macrophages in Hodgkin Lymphoma (cHL) and Diffuse Large B-cell Lymphoma (DLBCL). Levels of PD-1 on NK-cells were elevated in cHL relative to DLBCL. Read More

    Circulating tumor DNA reveals genetics, clonal evolution and residual disease in classical Hodgkin lymphoma.
    Blood 2018 Feb 15. Epub 2018 Feb 15.
    Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
    The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep-next-generation-sequencing approach for circulating tumor DNA (ctDNA), here we aimed at tracking the genetics of cHL in different clinical phases, and its modifications upon treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory cHL patients, including longitudinal samples collected under ABVD chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. Read More

    Fine tuning of FOXO3A in cHL as a survival mechanism and a hallmark of abortive plasma cell differentiation.
    Blood 2018 Feb 13. Epub 2018 Feb 13.
    Institute of Physiological Chemistry, University of Ulm, Ulm, Germany;
    We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin-Reed Sternberg (HRS) cells of cHL at higher levels than in Non-Hodgkin lymphoma (NHL) subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Read More

    Paraoxonase-2 regulates coagulation activation through endothelial tissue factor.
    Blood 2018 Feb 9. Epub 2018 Feb 9.
    Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany;
    Oxidative stress and inflammation of the vessel wall contribute to pro-thrombotic states. The anti-oxidative protein paraoxonase-2 (PON2) shows reduced expression in human atherosclerotic plaques and endothelial cells in particular. Supporting a direct role for Pon2 in cardiovascular diseases,-deficiency in mice promotes atherogenesis through incompletely understood mechanisms. Read More

    Enhancer dysfunction in leukemia.
    Blood 2018 Feb 9. Epub 2018 Feb 9.
    Cold Spring Harbor Laboratory, United States
    Hematopoietic cancers are often initiated by deregulation of the transcriptional machinery. Prominent among such regulators are the sequence-specific DNA-binding transcription factors (TFs), which bind to enhancer and promoter elements in the genome to control gene expression through the recruitment of cofactors. Remarkably, perturbing the function of even a single TF or cofactor can modulate the active enhancer landscape of a cell and, conversely, knowledge of the enhancer configuration can be used to discover functionally important TFs in a given cellular process. Read More

    Allele-selective RUNX1 binding regulates P1 blood group status by transcriptional control of.
    Blood 2018 Feb 8. Epub 2018 Feb 8.
    Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Biomedical Centre C14, Lund University, Lund, Sweden;
    P1 and Pare glycosphingolipid antigens synthesized by the-encoded α1,4-galactosyltransferase, using paragloboside and lactosylceramide as acceptor substrates, respectively. In addition to the compatibility aspects of these histo-blood group molecules, both constitute receptors for multiple microbes and toxins. Presence or absence of P1 antigen on erythrocytes determines the common P(P1+P+) and P(P1-P+) phenotypes. Read More

    How I treat myelodysplastic syndromes of childhood.
    Blood 2018 Feb 8. Epub 2018 Feb 8.
    Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Germany.
    Pediatric myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders with an annual incidence of 1-4 cases/million, accounting for less than 5% of childhood hematological malignancies. MDS in children often occur in the context of inherited bone marrow failure syndromes, this representing a peculiarity of myelodysplasia diagnosed in the pediatric age. Moreover, germline syndromes predisposing individuals to develop MDS/acute myeloid leukemia have recently been identified, such as those caused by mutations inandRefractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, showing specific histopathological features. Read More

    Integrated molecular profiling of juvenile myelomonocytic leukemia.
    Blood 2018 Feb 2. Epub 2018 Feb 2.
    Department of Pediatrics, Nagoya University Graduate School of Medicine, Japan;
    Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/myeloproliferative neoplasm occurring in infants and early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germline and somatic mutations in RAS pathway genes (e.g. Read More

    HO-1Patrolling Monocytes Protect against Vaso-occlusion in Sickle Cell Disease.
    Blood 2018 Feb 2. Epub 2018 Feb 2.
    Laboratory of Complement Biology, New York Blood Center, United States;
    Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated with vascular injury and dysfunction in mouse models, and painful vaso-occlusive crisis (VOC) involving increased attachment of sickle erythrocytes and activated leukocytes to damaged vascular endothelium. Patrolling monocytes, which normally scavenge damaged cells and debris from the vasculature, express higher levels of anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Here, we show that HO-1-expressing patrolling monocytes protect SCD vasculature from ongoing hemolytic insult and vaso-occlusion. Read More

    α-Antitrypsin Infusion for treatment of Steroid Resistant Acute Graft-versus-Host Disease.
    Blood 2018 Feb 2. Epub 2018 Feb 2.
    Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States;
    Corticosteroid resistance following acute GVHD (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness due to poor response or excessive toxicity, primarily from infection. Alpha-1 antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by down-modulation of inflammation and increasing ratios of regulatory to effector T cells. Read More

    Single-Agent Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia: A 5-Year Experience.
    Blood 2018 Feb 2. Epub 2018 Feb 2.
    The Ohio State University, Columbus, OH, United States.
    We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naive (TN) older patients (≥65 years) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N=31) and R/R (N=101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN and 10% in R/R patients. Read More

    B-cell targeting in chronic Graft-versus-Host disease.
    Blood 2018 Feb 1. Epub 2018 Feb 1.
    Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, United States.
    Over the last decade our understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) has improved considerably. In this spotlight, we discuss emerging insights into the pathophysiology of cGVHD with a focus on B-cells. First, we summarize supporting evidence derived from mouse and human studies. Read More

    Prognostic value of baseline metabolic tumor volume in early stage Hodgkin's lymphoma in the standard arm of H10 trial.
    Blood 2018 Feb 1. Epub 2018 Feb 1.
    LYSA Imaging, Creteil, France.
    We tested baseline PET/CT as a measure of total tumor burden in order to better identify high risk patients in early-stage Hodgkin's lymphoma (HL). Stage I-II HL patients enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after two cycles of doxorubicine, bleomycin, vinblastine, dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. Read More

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