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Current Opinion in Hematology

Charlene V Chabata, James W Frederiksen, Bruce A Sullenger, Ruwan Gunaratne
PURPOSE OF REVIEW: Since the selection of the first thrombin-binding aptamer in 1992, the use of nucleic acid aptamers to target specific coagulation factors has emerged as a valuable approach for generating novel anticoagulant and procoagulant therapeutics. Herein, we highlight the most recent discoveries involving application of aptamers for those purposes. RECENT FINDINGS: Learning from the successes and pitfalls of the FIXa-targeting aptamer pegnivacogin in preclinical and clinical studies, the latest efforts to develop antidote-controllable anticoagulation strategies for cardiopulmonary bypass that avoid unfractionated heparin involve potentiation of the exosite-binding factor X (FX)a aptamer 11F7t by combination with either a small molecule FXa catalytic site inhibitor or a thrombin aptamer...
July 12, 2018: Current Opinion in Hematology
June Li, Jade A Sullivan, Heyu Ni
PURPOSE OF REVIEW: Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder with as of yet, no established clinical prognostic or diagnostic biomarkers. Patients frequently experience a markedly decreased quality of life and may be at risk for severe/fatal haemorrhage. Here, we address discoveries in the pathogenesis of ITP, and novel therapeutic strategies in mouse models and human patients. Consolidation of these findings should be important in providing insight to establish future prognostic protocols as well as cutting-edge therapeutics to target refractory ITP...
July 12, 2018: Current Opinion in Hematology
Evi X Stavrou
PURPOSE OF REVIEW: This review describes the contribution of coagulation factor XII (FXII) in sterile inflammation and wound healing, focusing on recently identified roles for zymogen FXII in neutrophil functions. RECENT FINDINGS: Recent studies have identified an important role for FXII in neutrophil trafficking. In particular, following neutrophil activation, autocrine FXII signals through the urokinase plasminogen activator receptor (uPAR) on the neutrophil surface to upregulate neutrophil functions...
July 9, 2018: Current Opinion in Hematology
David W Essex, Yi Wu
PURPOSE OF REVIEW: The present review provides an overview of recent findings on new members of the protein disulfide isomerase (PDI) family required for thrombosis. RECENT FINDINGS: Twenty years ago PDI was shown to mediate platelet aggregation, and 10 years ago PDI was shown to support thrombosis in vivo. Subsequently, other members of this endoplasmic reticulum family of enzymes, ERp57 and ERp5, were demonstrated to support thrombosis. A fourth member, ERp72, was recently shown to be required for platelet accumulation and fibrin deposition in vivo...
July 9, 2018: Current Opinion in Hematology
Alexandra Sherman, Moanaro Biswas, Roland W Herzog
PURPOSE OF REVIEW: Hemophilia is an X-linked blood coagulation genetic disorder, which can cause significant disability. Replacement therapy for coagulation factor VIII (hemophilia A) or factor IX (hemophilia B) may result in the development of high-affinity alloantibodies ('inhibitors') to the replacement therapy, thus making it ineffective. Therefore, there is interest in directing immunological responses towards tolerance to infused factors. RECENT FINDINGS: In this review, we will discuss latest advancements in the development of potentially less immunogenic replacement clotting factors, optimization of current tolerance induction protocols (ITI), preclinical and clinical data of pharmacological immune modulation, hepatic gene therapy, and the rapidly advancing field of cell therapies...
July 9, 2018: Current Opinion in Hematology
Alisa S Wolberg
PURPOSE OF REVIEW: In spite of significant morbidity and mortality associated with venous thromboembolism, the underlying pathogenesis remains poorly understood. RECENT FINDINGS: Clues to operant pathogenic mechanisms are found in the unique morphology and composition of these thrombi, which have substantial red blood cell and fibrin content. Recent studies have revealed biochemical and biophysical mechanisms that dictate fibrin structure in venous thrombi and promote retention of red blood cells within the contracted clots...
July 9, 2018: Current Opinion in Hematology
Harvey G Roweth, Somayje Parvin, Kellie R Machlus
PURPOSE OF REVIEW: Platelets are small, anucleate cells that circulate within the blood and play essential roles in preserving vascular integrity. However, abnormalities in either platelet production or destruction can result in thrombocytopenia, clinically defined by a platelet count lower than 150 000/μL of whole blood. Thrombocytopenia is frequently associated with impaired hemostatic responses to vascular injury and can be life-threatening because of bleeding complications. Megakaryocytes are the precursor cells responsible for platelet production, a process commonly referred to as thrombopoiesis...
July 4, 2018: Current Opinion in Hematology
Michael Boyiadzis, Theresa L Whiteside
PURPOSE OF REVIEW: Exosomes are cell-derived, biologically active membrane-bound vesicles, and are emerging as key modulators of hematopoiesis. Recent studies have provided a clearer understanding of the mechanisms whereby blast-derived exosomes act to suppress hematopoiesis in acute myeloid leukemia (AML). RECENT FINDINGS: Exosomes released from leukemia blasts have been shown to suppress hematopoietic progenitor cell (HPC) functions indirectly through stromal reprogramming of niche-retention factors and also as a consequence of AML exosome-directed microRNA delivery to HPC...
July 2018: Current Opinion in Hematology
Vijay Menon, Saghi Ghaffari
PURPOSE OF REVIEW: Work in the past decade has revealed key functions of the evolutionary conserved transcription factors Forkhead box O (FOXO) in the maintenance of homeostatic hematopoiesis. Here the diverse array of FOXO functions in normal and diseased hematopoietic stem and progenitor cells is reviewed and the main findings in the past decade are highlighted. Future work should reveal FOXO-regulated networks whose alterations contribute to hematological disorders. RECENT FINDINGS: Recent studies have identified unanticipated FOXO functions in hematopoiesis including in hematopoietic stem and progenitor cells (HSPC), erythroid cells, and immune cells...
July 2018: Current Opinion in Hematology
Léa Verdière, Frédéric Mourcin, Karin Tarte
PURPOSE OF REVIEW: In addition to the recent progresses in the description of the genetic landscape of B-cell non-Hodgkin's lymphomas, tumor microenvironment has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, drug resistance, and late progression/transformation. The purpose of this review is to outline the most recent findings regarding malignant B-cell niche composition and organization supporting direct and indirect tumor-promoting functions of lymphoma microenvironment...
July 2018: Current Opinion in Hematology
James A Heward, Emil A Kumar, Koorosh Korfi, Jessica Okosun, Jude Fitzgibbon
PURPOSE OF REVIEW: The treatment of the germinal center lymphomas, diffuse large B cell (DLBCL) and follicular lymphoma, has changed little beyond the introduction of immunochemotherapies. However, there exists a substantial group of patients within both diseases for which improvements in care will involve appropriate tailoring of treatment. RECENT FINDINGS: DLBCL consists of two major subtypes with striking differences in their clinical outcomes paralleling their underlying genetic heterogeneity...
July 2018: Current Opinion in Hematology
Renée Beekman, Virginia Amador, Elias Campo
PURPOSE OF REVIEW: SOX11 has emerged as a key transcription factor in the pathogenesis of mantle cell lymphoma (MCL) whereas it is not expressed in normal B cells or virtually in any other mature B-cell neoplasm. This review will examine the role of SOX11 as a biomarker in MCL, the new information on its transcriptional targets, and the mechanisms regulating its expression in MCL. RECENT FINDINGS: SOX11 is highly expressed in conventional MCL, including cyclin D1-negative cases, but it is not expressed in the indolent leukemic nonnodal MCL subtype...
July 2018: Current Opinion in Hematology
Jennifer R Shingleton, Sandeep S Dave
PURPOSE OF REVIEW: We review the genetic foundations of different rare lymphomas to examine their shared origins. These data indicate the potential application of genomics to improve the diagnosis and treatment of these rare diseases. RECENT FINDINGS: Next generation sequencing technologies have provided an important window into the genetic underpinnings of lymphomas. A growing body of evidence indicates that although some genetic alterations are specific to certain diseases, others are shared across different lymphomas...
July 2018: Current Opinion in Hematology
Charles Durand, Pierre Charbord, Thierry Jaffredo
PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) reside in specific microenvironments also called niches that regulate HSC functions. Understanding the molecular and cellular mechanisms involved in the crosstalk between HSCs and niche cells is a major issue in stem cell biology and regenerative medicine. The purpose of this review is to discuss recent advances in this field with particular emphasis on the transcriptional landscape of HSC niche cells and the roles of extracellular vesicles (EVs) in the dialog between HSCs and their microenvironments...
July 2018: Current Opinion in Hematology
Sergi Cuartero, Matthias Merkenschlager
PURPOSE OF REVIEW: The three-dimensional organization of the genome inside the nucleus impacts on key aspects of genome function, including transcription, DNA replication and repair. The chromosome maintenance complex cohesin and the DNA binding protein CTCF cooperate to drive the formation of self-interacting topological domains. This facilitates transcriptional regulation via enhancer-promoter interactions, controls the distribution and release of torsional strain, and affects the frequency with which particular translocations arise, based on the spatial proximity of translocation partners...
July 2018: Current Opinion in Hematology
Gero Knittel, Tim Rehkämper, Pascal Nieper, Anna Schmitt, Ruth Flümann, H Christian Reinhardt
PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity...
July 2018: Current Opinion in Hematology
Kyunghee Choi
PURPOSE OF REVIEW: Recent studies have established that haematopoietic stem cells (HSCs) remain quiescent in homeostatic conditions, and minimally contribute to haematopoietic homeostasis. However, they undergo extensive cell cycle and expansion upon bone marrow transplantation or haematopoietic injury to reestablish the haematopoietic system. Molecular basis for the HSC activation and expansion is not completely understood. Here, we review the recent study elucidating the role of the developmentally critical Ets transcription factor Etv2 in reestablishing haematopoietic system upon injury through promoting HSC regeneration...
July 2018: Current Opinion in Hematology
Mathew G Angelos, Dan S Kaufman
PURPOSE OF REVIEW: We summarize current advances to define the role the aryl hydrocarbon receptor (AHR) plays in mammalian hematopoiesis. We emphasize approaches to modulate AHR throughout human hematopoietic development in vitro to support the production of clinically relevant blood products suitable for patient care. RECENT FINDINGS: Initial data demonstrate that both pharmacologic AHR inhibition and genetic deletion from human pluripotent stem cells provide useful strategies to enhance the yield of hematopoietic stem and progenitor cells...
July 2018: Current Opinion in Hematology
Roman Galeev, Jonas Larsson
PURPOSE OF REVIEW: Disturbance of the delicate balance between self-renewal and differentiation in haematopoietic stem cells (HSCs) can lead to both leukaemia and bone marrow failure. The regulation of this balance in HSC biology has been intensely investigated in several model systems, and lately the importance of epigenetic modifications as well as the organization and architecture of chromatin has become increasingly recognized. In this review, we will focus on the role of the chromatin organizing protein complex cohesin in regulation of normal and malignant haematopoiesis...
July 2018: Current Opinion in Hematology
Cuiping Zhang, Ying Liang
PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) produce mature blood cells throughout lifetime. Natural genetic diversity offers an important yet largely untapped reservoir for deciphering regulatory mechanisms of HSCs and hematopoiesis. In this review, we explore the role of latexin, identified by natural variation, in regulating homeostatic and stress hematopoiesis, unravel the underlying signaling pathways, and propose its therapeutic implication. RECENT FINDINGS: Latexin acts endogenously in HSCs to negatively regulate their population size by enhancing apoptosis and by decreasing self-renewal...
July 2018: Current Opinion in Hematology
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