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Pallavi Galera, Amy P Hsu, Weixin Wang, Stephenie Droll, Rui Chen, Jason R Schwartz, Jeffery M Klco, Sally Arai, Luke Maese, Christa Zerbe, Mark J Parta, Neal S Young, Steven M Holland, Dennis D Hickstein, Katherine R Calvo
No abstract text is available yet for this article.
September 19, 2018: Blood
Shiro Tara, Yusuke Isshiki, Yaeko Nakajima-Takagi, Motohiko Oshima, Kazumasa Aoyama, Tomoyuki Tanaka, Daisuke Shinoda, Shuhei Koide, Atsunori Saraya, Satoru Miyagi, Ichiro Manabe, Hirotaka Matsui, Haruhiko Koseki, Vivian J Bardwell, Atsushi Iwama
BCOR , encoding BCL-6 co-repressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 ( BcorΔE4/y ) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 ( BcorΔE9-10/y ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex (PRC) 1...
September 18, 2018: Blood
Scott J Cameron, Hannah Russell, A Phillip Owens
Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150,000 new cases and nearly 15,000 deaths annually, the only approved treatment for AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. As most clinically-relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression...
September 18, 2018: Blood
Pasquale L Fedele, Simon N Willis, Yang Liao, Michael S Low, Jai Rautela, David H Segal, Jia-Nan Gong, Nicholas D Huntington, Wei Shi, David C S Huang, George Grigoriadis, Julie Tellier, Stephen L Nutt
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis...
September 18, 2018: Blood
Anna Chorzalska, John Morgan, Nagib Ahsan, Diana O Treaba, Adam J Olszewski, Max Petersen, Nathan Kingston, Yan Cheng, Kara Lombardo, Christoph Schorl, Xiaoqing Yu, Roberta Zini, Annalisa Pacilli, Alexander Tepper, Jillian Coburn, Anita Hryniewicz-Jankowska, Ting C Zhao, Elena Oancea, John L Reagan, Olin Liang, Leszek Kotula, Peter J Quesenberry, Philip A Gruppuso, Rossella Manfredini, Alessandro Maria Vannucchi, Patrycja M Dubielecka
Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors neither have curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of Abi1 in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF...
September 13, 2018: Blood
Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T Nurden, Ernest Turro, Willem H Ouwehand, Cécile V Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, Marijke Bryckaert
The ephrin transmembrane receptor (EPHR) family of tyrosine kinases is involved in platelet function. We report the first EPHB2 variant affecting platelets in two siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation and granule secretion induced by GPCR (G protein-coupled receptors) agonists and convulxin as well as in thrombus formation on collagen under flow...
September 13, 2018: Blood
Katerina Musilova, Jan Devan, Katerina Cerna, Vaclav Seda, Gabriela Pavlasova, Sonali Sharma, Jan Oppelt, Robert Pytlik, Vit Prochazka, Zuzana Prouzova, Martin Trbusek, Lenka Zlamalikova, Kvetoslava Liskova, Lenka Kruzova, Marie Jarosova, Andrea Mareckova, Christoph Kornauth, Ingrid Simonitsch-Klupp, Ana-Iris Schiefer, Olaf Merkel, Heidi Mocikova, Pavel Burda, Katerina Machova Polakova, Leos Kren, Jiri Mayer, Clive S Zent, Marek Trneny, Andrew G Evans, Andrea Janikova, Marek Mraz
Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma (DLBCL). Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying FL transformation are unclear. Here we performed the first profiling of miRNAs' expression in paired samples of FL and tFL and identified five miRNAs as being differentially expressed...
September 13, 2018: Blood
Iris de Weerdt, Tom Hofland, Roeland Lameris, Sanne Endstra, Aldo Jongejan, Perry Moerland, Renee Cg de Bruin, Ester B M Remmerswaal, Ineke J M Ten Berge, Nora Liu, Mario van der Stelt, Laura M Faber, Mark-David Levin, Eric Eldering, Sanne H Tonino, Tanja D de Gruijl, Hans J van der Vliet, Arnon P Kater
The efficacy of autologous (αβ)-T cell-based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2T-cell subset comprises of cytotoxic T lymphocytes with potent anti-lymphoma activity via a major histocompatibility complex (MHC)-independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control (HC) Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset...
September 13, 2018: Blood
Carine Fillebeen, Nicole Wilkinson, Edouard Charlebois, Angeliki Katsarou, John Wagner, Kostas Pantopoulos
Systemic iron balance is controlled by hepcidin, a liver hormone that limits iron efflux to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells. Iron-dependent hepcidin induction requires hemojuvelin (HJV), a bone morphogenetic protein (BMP) co-receptor that is disrupted in juvenile hemochromatosis, causing dramatic hepcidin deficiency and tissue iron overload. Hjv-/- mice recapitulate phenotypic hallmarks of hemochromatosis but exhibit blunted hepcidin induction following lipopolysaccharide (LPS) administration...
September 13, 2018: Blood
De-Liang Zhang, Manik C Ghosh, Hayden Ollivierre, Yan Li, Tracey A Rouault
Ferroportin (FPN), the only known vertebrate iron exporter, transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues and cells in vivo. Most of the circulating iron is consumed by erythroid cells to synthesize hemoglobin. Here we found that erythroid cells not only consumed large amounts of iron, but also returned significant amounts of iron to the blood. Erythroblast-specific Fpn knockout (Fpn KO) mice developed lower serum iron levels in conjunction with tissue iron overload, and increased FPN expression in spleen and liver without changing hepcidin levels...
September 13, 2018: Blood
Li Li, Jun Zhang, Juan Chen, Zijun Y Xu-Monette, Yi Miao, Min Xiao, Ken H Young, Sa Wang, L Jeffrey Medeiros, Michael Wang, Richard J Ford, Lan V Pham
Knowledge of PD-L1 expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-PD-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may also identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression...
September 12, 2018: Blood
Haiying Qin, Kazusa Ishii, Sang Nguyen, Paul P Su, Chad R Burk, Bong-Hyun Kim, Brynn B Duncan, Samikasha Tarun, Nirali N Shah, M Eric Kohler, Terry J Fry
Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CART) has demonstrated dramatic success in relapsed/refractory pre-B cell ALL but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T cell function but this has not been well studied in ALL and in the context of CAR expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T cell function in vivo. Vaccines protect against TCF3/PBX1...
September 12, 2018: Blood
Neha Mehta-Shah, Mark W Clemens, Steven M Horwitz
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently described form of T-cell non-Hodgkin lymphoma now formally recognized by the World Health Organization classification of lymphoid neoplasms. The disease most often presents with a delayed seroma around the breast implant, almost exclusively one with a textured surface, and manifests with breast pain, swelling or asymmetry, capsular contracture, but can also present with a breast mass, and lymph node involvement. The prognosis of BIA-ALCL is favorable compared to many other subtypes of systemic T-cell lymphoma, however unlike other non-Hodgkin lymphomas, complete surgical excision for localized disease is an important part of the management of these patients...
September 12, 2018: Blood
Irene Artuso, Maria Rosa Lidonnici, Sandro Altamura, Giacomo Mandelli, Mariateresa Pettinato, Martina U Muckenthaler, Laura Silvestri, Giuliana Ferrari, Clara Camaschella, Antonella Nai
β-thalassemias are genetic disorders characterized by anemia, ineffective erythropoiesis and iron overload. Current treatment of severe cases is based on blood transfusion and iron chelation or allogeneic bone marrow transplantation. Novel approaches are explored for non-transfusion-dependent patients (thalassemia intermedia) who develop anemia and iron overload. Here we investigated the erythropoietin receptor partner, Transferrin Receptor 2 (TFR2), as a novel potential therapeutic target. We generated a murine model of thalassemia intermedia specifically lacking bone marrow Tfr2: being their erythroid cells more susceptible to erythropoietin stimulation, mice show improved erythropoiesis and red blood cells morphology and partial correction of anemia and iron-overload...
September 12, 2018: Blood
Ali T Taher, Maria Domenica Cappellini
The complex pathophysiology in beta-thalassemia can translate to multiple morbidities that affect every organ system. Improved survival due to advances in management meant that patients are exposed to the harmful effects of ineffective erythropoiesis, anemia and iron overload for a longer duration, and we started seeing new or more frequent complications in adult compared with younger patients. In this article, we highlight particular aspects of managing adult patients with beta-thalassemia utilizing our own experience in treating such patients...
September 11, 2018: Blood
Swee Lay Thein, Jo Howard
With increasing survival, cumulative complications of sickle cell disease (SCD) which develop insidiously over time, are becoming more apparent and common in older patients, particularly those in their fifth decade and beyond. The older patient is also more likely to develop other age-related non-sickle conditions that interact and add to the disease morbidity. A common misconception is that any symptom in a SCD patient is attributable to their SCD and this may lead to delays in diagnosis and appropriate intervention...
September 11, 2018: Blood
Evans M Machogu, Roberto F Machado
Hemoglobinopathies are caused by genetic mutations that result in abnormal hemoglobin molecules that result in hemolytic anemia. Chronic complications involving the lung parenchyma, vasculature and cardiac function in hemoglobinopathies result in impaired gas exchange resulting in tissue hypoxia. Hypoxia is defined as the deficiency in the amount of oxygen reaching the tissues of the body and is prevalent in patients with hemoglobinopathies and its cause is often multifactorial. Chronic hypoxia in hemoglobinopathies is often a sign of disease severity and is associated with increased morbidity and mortality...
September 11, 2018: Blood
Thomas D Coates
No abstract text is available yet for this article.
September 11, 2018: Blood
Matthieu Jestin, Ygal Benhamou, An-Sofie Schelpe, Elien Roose, François Provôt, Lionel Galicier, Miguel Hié, Claire Presne, Pascale Poullin, Alain Wynckel, Samir Saheb, Christophe Deligny, Aude Servais, Stéphane Girault, Yahsou Delmas, Tarik Kanouni, Alexandre Lautrette, Dominique Chauveau, Christiane Mousson, Pierre Perez, Jean-Michel Halimi, Anne Charvet-Rumpler, Mohamed Hamidou, Pascal Cathébras, Karen Vanhoorelbeke, Agnès Veyradier, Paul Coppo
Preemptive rituximab infusions prevent relapses in immune thrombotic thrombocytopenic purpura (iTTP) by maintaining normal ADAMTS13 activity. However, the long-term outcome of these patients and the potential adverse events of this strategy need to be determined. We report the long-term outcome of 92 patients with iTTP in clinical remission who received preemptive rituximab after identification of severe ADAMTS13 deficiency (activity <10%) during the follow-up. Thirty-seven patients had >1 iTTP episode, and the median cumulative relapse incidence before preemptive rituximab was 0...
September 10, 2018: Blood
Jean M Connors
Direct oral anticoagulants (DOAC) have significantly improved the care of patients requiring anticoagulation. With similar or better efficacy and safety outcomes, and easier use in the outpatient setting compared to the standard of care vitamin K antagonists (VKA) and low molecular weight heparin (LMWH), DOAC are now endorsed as first line treatment for indications including prevention of stroke and systemic embolism in non-valvular AF and treatment of VTE. DOAC are easy to use oral agents that offer simple dosing , short half-lives, with no need to test levels due to the wide therapeutic window and limited drug-drug interactions...
September 10, 2018: Blood
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