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    Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge.
    Blood 2017 Oct 11. Epub 2017 Oct 11.
    IRSD, Universite de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.
    Lack of either BMP6 or the BMP co-receptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin insufficiency, hepatic iron loading, and extrahepatic iron accumulation in males. This is consistent with the current views that HJV is a co-receptor for BMP6 in hepatocytes. To determine whether BMP6 and HJV may also signal to hepcidin independently of each other, we intercrossed Hjv(-/-) and Bmp6(-/-) mice and compared the phenotype of animals of the F2 progeny. Read More

    Gemtuzumab ozogamicin for acute myeloid leukemia.
    Blood 2017 Oct 11. Epub 2017 Oct 11.
    Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
    On September 1, 2017, the U.S. Food and Drug Administration (FDA) approved gemtuzumab ozogamicin for the treatment of adults with newly diagnosed CD33+ acute myeloid leukemia and for patients aged 2 years and older with CD33+ AML who have experienced a relapse or who have not responded to initial treatment. Read More

    In vivo generated thrombin and plasmin do not activate the complement system in baboons.
    Blood 2017 Oct 11. Epub 2017 Oct 11.
    Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
    Sepsis concurrently activate both coagulation and complement systems. While complement activation by bacteria is well-documented, work in mice and in vitro suggests that coagulation proteases can directly cleave complement proteins. We aimed to determine if generation of coagulation proteases in vivo can activate the complement cascade in two highly coagulopathic models. Read More

    Immune Reconstitution and Survival of 100 SCID Patients Post Hematopoietic Cell Transplant: A PIDTC Natural History Study.
    Blood 2017 Oct 11. Epub 2017 Oct 11.
    University of California, San Francisco, United States.
    The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010-2014, including 68 with typical SCID and 32 with leaky SCID, Omenn Syndrome or Reticular Dysgenesis. Most (59%) were diagnosed by newborn screening or family history. Read More

    The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.
    Blood 2017 Oct 10. Epub 2017 Oct 10.
    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
    The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA binding subunits of the macromolecular complex, direct repeat erythroid-definitive (DRED), which has been shown to repress ϵ- and γ- globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr4(+/-) mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Read More

    Platelet interaction with activated endothelium: mechanistic insights from microfluidics.
    Blood 2017 Oct 10. Epub 2017 Oct 10.
    Department of Biochemistry, CARIM School for Cardiovascular Research, Maastricht University, Maastricht, Netherlands
    Traditionally, in vitro flow chamber experiments and in vivo arterial thrombosis studies have been proven to be of vital importance to elucidate the mechanisms of platelet thrombus formation after vessel wall injury. In recent years, it has become clear that platelets also act as modulators of inflammatory processes, such as atherosclerosis. A key element herein is the complex crosstalk between platelets, the coagulation system, leukocytes and the activated endothelium. Read More

    CHD7 deficiency delays leukemogenesis in mice induced by CBFB-MYH11.
    Blood 2017 Oct 10. Epub 2017 Oct 10.
    Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States;
    Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFβ-SMMHC (encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain-helicase-DNA binding protein 7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. Read More

    SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia.
    Blood 2017 Oct 10. Epub 2017 Oct 10.
    Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States;
    Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, L-asparaginase. H3K36me3 localizes components of the DNA damage response pathway and SETD2 mutation impaired the DNA damage response (DDR), blunting apoptosis induced by cytotoxic chemotherapy. Read More

    Novel approaches to hemophilia therapy: successes and challenges.
    Blood 2017 Oct 10. Epub 2017 Oct 10.
    The Children's Hospital of Philadelphia, Philadelphia, PA, United States Minor Outlying Islands.
    New therapies for hemophilia A and hemophilia B will likely continue to change clinical practice. Ranging from extended half-life to non-factor products and gene therapy, these innovative approaches have the potential to enhance the standard of care by decreasing infusion frequency to increase compliance, promoting prophylaxis, offering alternatives to inhibitor patients, and easing route of administration. Each category has intrinsic challenges that may limit the broader application of these promising therapies. Read More

    Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma.
    Blood 2017 Oct 10. Epub 2017 Oct 10.
    Centre Hospitalier Universitaire (CHU) de Nantes, INSERM, Universite de Nantes, France.
    Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in MM cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase I study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Read More

    NK cell recovery after haploidentical HSCT with post-transplant cyclophosphamide: dynamics and clinical implications.
    Blood 2017 Oct 6. Epub 2017 Oct 6.
    Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
    The use of post-transplant cyclophosphamide (PT-Cy) as GvHD prophylaxis has revolutionized haploidentical HSCT, allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects NK cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in two independent centers. Read More

    Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia.
    Blood 2017 Oct 9;130(14):1620-1627. Epub 2017 Aug 9.
    Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD.
    Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Read More

    Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia.
    Blood 2017 Oct 4. Epub 2017 Oct 4.
    Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    A number of studies have recently demonstrated that "super-enhancers", which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. Identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. Read More

    Marginal zone B cells are critical to factor VIII inhibitor formation in mice with hemophilia A.
    Blood 2017 Oct 4. Epub 2017 Oct 4.
    Center for Transfusion Medicine and Cellular Therapies, Dept. of Laboratory Medicine and Pathology, Emory University School of Medicine, Atlanta, GA, United States;
    While factor VIII (FVIII) replacement therapy can be life saving for patients with hemophilia A, neutralizing alloantibodies to FVIII, known as inhibitors, develop in a significant number of patients and actively block FVIII activity, making bleeding difficult to control and prevent. Although a variety of downstream immune factors likely regulate inhibitor formation, the identification and subsequent targeting of key initiators in inhibitor development may provide an attractive approach to prevent inhibitor formation before amplification of the FVIII immune response occurs. As the initial steps in FVIII inhibitor development remain incompletely understood, we sought to define early regulators of FVIII inhibitor formation. Read More

    Impact of extracellular fluid tonicity on sickle red blood cell deformability and adhesion.
    Blood 2017 Oct 4. Epub 2017 Oct 4.
    Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer & Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, United States;
    Abnormal sickle red blood cell (sRBC) biomechanics, including pathological deformability and adhesion, correlate with clinical severity in sickle cell disease (SCD). Clinical intravenous fluids (IVFs) of various tonicities are often used during treatment of vaso-occlusive pain episodes (VOE), the major cause of morbidity in SCD. However, evidence-based guidelines are lacking and there is no consensus regarding which IVFs to use during VOE. Read More

    Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma.
    Blood 2017 Oct 3. Epub 2017 Oct 3.
    University of Washington Medical Center, Seattle, WA, United States.
    This pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (N=58), no progressions were observed beyond 40 months, and median OS was not reached. Read More

    Hematopoietic stem cell transplantation rescues the hematological, immunological and vascular phenotype in DADA2.
    Blood 2017 Oct 3. Epub 2017 Oct 3.
    Department of Pediatrics, Division of immunology, University Hospitals of Leuven, Leuven, Belgium;
    Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1 DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes and intracranial hemorrhages), immunodeficiency and bone marrow failure. TNF-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. Read More

    Philadelphia chromosome-like acute lymphoblastic leukemia.
    Blood 2017 Oct 2. Epub 2017 Oct 2.
    Department of Pediatrics and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States;
    Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; also referred to as BCR-ABL1-like ALL) is a high risk subset with a gene expression profile that shares significant overlap with that of Philadelphia chromosome positive (Ph(+)) ALL and is suggestive of activated kinase signaling. While Ph(+) ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1, and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Read More

    Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients.
    Blood 2017 Oct 2. Epub 2017 Oct 2.
    Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States;
    The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the anti-apoptotic mediator BCL2 as a potential therapeutic target. Read More

    First in human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia.
    Blood 2017 Sep 27. Epub 2017 Sep 27.
    Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria;
    T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with a short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 FDA-approved anti-cancer drugs or compounds currently in clinical development we pursued to identify novel effective treatments for T-PLL patients. We found that the BCL-2 inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Read More

    Procoagulant Platelets:-Generation, Function and Therapeutic Targeting in Thrombosis.
    Blood 2017 Sep 27. Epub 2017 Sep 27.
    School of Physiology, Pharmacology and Neuroscience, University of Bristol, United Kingdom.
    Current understanding of how platelets localise coagulation to wound sites has come mainly from studies of a subpopulation of activated platelets. In this review we summarise data from the last four decades which has described these platelets with a range of descriptive titles and attributes. We identify striking overlaps in the reported characteristics of these platelets which imply a single subpopulation of versatile platelets, and thus suggest that their commonality requires unification of their description. Read More

    A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice.
    Blood 2017 Sep 29. Epub 2017 Sep 29.
    Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia;
    T cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TEC. Guided by gene expression profiling, we created mouse models which specifically deleted pro-survival genes in TEC. Read More

    Effective 'Activated PI3Kδ Syndrome'-targeted therapy with the PI3Kδ inhibitor leniolisib.
    Blood 2017 Sep 29. Epub 2017 Sep 29.
    Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
    Pathogenic gain-of-function variants in the genes encoding PI3Kδ (phosphoinositide 3-kinase delta) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy and immune-deficiency (Activated PI3Kδ Syndrome, APDS). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Read More

    Thyroid hormone regulates hematopoiesis via the TR-KLF9 axis.
    Blood 2017 Sep 25. Epub 2017 Sep 25.
    State Key Laboratory of Stem cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
    Congenital hypothyroidism (CH) is one of the most prevalent endocrine diseases and is often accompanied by anemia and immunodeficiency in patients, for which the underlying mechanisms remain unknown. Here we created a severe CH model together with anemia and T lymphopenia to mimic the clinical features of hypothyroid patients by ethylnitrosourea (ENU) mutagenesis in Bama miniature pigs. A novel recessive c. Read More




    Confirmed efficacy of etoposide and dexamethasone in HLH treatment: Long term results of the cooperative HLH-2004 study.
    Blood 2017 Sep 21. Epub 2017 Sep 21.
    Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden;
    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% CI, 48-60%), systemic therapy included etoposide, dexamethasone and, from week nine, cyclosporine A (CSA). HSCT was indicated in patients with familial/genetic, relapsing, or severe and persistent disease. Read More

    Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia.
    Blood 2017 Sep 21. Epub 2017 Sep 21.
    Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
    Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). Read More

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