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Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell diseaseOpen in a New Window

Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs) which accelerates their hemolysis. (Ramasamy Jagadeeswaran, Benjamin A. Vazquez, Muthusamy Thiruppathi, Balaji B. Ganesh, Vinzon Ibanez, Shuaiying Cui, James D. Engel, Alan M. Diamond, Robert E. Molokie, Joseph DeSimone, Donald Lavelle, Angela Rivers) - 2017-02-23

 

Rat acute GvHD is Th1-driven and characterized by predominant donor CD4 T cell infiltration of skin and gutOpen in a New Window

Acute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of allo-activated donor T cells primarily into the gastrointestinal tract and skin. While cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete immunoregulatory cytokines. Acute GvHD is thought to be primarily initiated by Th1 cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. (Margherita Boieri, Pranali Shah, Dasaradha Jalapothu, Olena Zaitseva, Lutz Walter, Bent Rolstad, Christian Naper, Ralf Dressel, Marit Inngjerdingen) - 2017-02-23

 

The Calreticulin control of human stress erythropoiesis is impaired by V617F in polycythemia veraOpen in a New Window

Calreticulin is a Ca2+ binding protein that shuttle among cellular compartments with proteins bound to its N/P- domains. The knowledge that activation of the human erythropoietin receptor induces Ca2+-fluxes suggested us to investigate the role of calreticulin in human erythropoiesis. By western-blot, erythroblasts generated in-vitro from normal sources and JAK2V617F polycythemia vera (PV) patients expressed robust levels of calreticulin. However, Ca2+ regulated calreticulin conformation only in normal cells. (Mario Falchi, Lilian Varricchio, Fabrizio Martelli, Manuela Marra, Orietta Picconi, Agostino Tafuri, Gabriella Girelli, Vladimir N. Uversky, Anna Rita Migliaccio) - 2017-02-20

 

The Evolving View of the Hematopoietic Stem Cell NicheOpen in a New Window

Hematopoietic stem cells (HSC) reside in specialized microenvironments known as niches. The niche is essential to support HSC function and to maintain a correct balance between self-renewal and differentiation. Recent advances in defining different mesenchymal and endothelial bone marrow cell populations as well as hematopoietic stem and progenitor cells greatly enhanced our understanding of these niches and of the molecular mechanisms by which they regulate HSC function. In addition to the role in maintaining HSCs homeostasis, the niche has also been implicated in the pathogenesis of blood disorders including hematological malignancies. (Isabel Beerman, Tiago C. Luis, Sofie Singbrant, Cristina Lo Celso, Simon Méndez-Ferrer) - 2017-02-10

 

Chromatin priming of genes in development: concepts, mechanisms and consequencesOpen in a New Window

During ontogeny, cells progress through multiple alternate differentiation states by activating distinct gene regulatory networks. In this review we highlight the important role of chromatin priming in facilitating gene activation during lineage specification and in maintaining an epigenetic memory of previous gene activation. We describe that chromatin priming is part of a hugely diverse repertoire of regulatory mechanisms that genes use to ensure that they are expressed at the correct time, in the correct cell type, at the correct level, but also that they react to signals. (Constanze Bonifer, Peter N. Cockerill) - 2017-02-06

 

Application of vitamin D and vitamin D analogs in acute myelogenous leukemiaOpen in a New Window

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant transformed immature hematopoietic myeloid precursors that have lost their ability to differentiate and proliferate normally. Current treatment for acute myeloid leukemia (AML) requires intensive cytotoxic chemotherapy and results in significant morbidity and mortality, especially in older patients. Effective and better-tolerated treatment is urgently needed. Studies have shown that 1α,25-Dihydroxyvitamin D3 (1,25-D3, active VD3) or vitamin D analogs (VDAs) can potently differentiate AML cells in vitro and ex vivo, which led to early clinical trials in AML and myelodysplastic syndrome patients. (Huynh Cao, Yi Xu, Rosalia de Necochea-Campion, David J. Baylink, Kimberly J. Payne, Xiaolei Tang, Christina Ratanatharathorn, Yong Ji, Saied Mirshahidi, Chien-Shing Chen) - 2017-02-04

 

Impact of TET2 Deficiency on Iron Metabolism in ErythroblastsOpen in a New Window

Sideroblastic anemia is characterized by the presence of ring sideroblasts, which are caused by iron accumulation in the mitochondria of erythroblasts and are present in both acquired and congenital forms of sideroblastic anemia. However, the mechanism leading to ring sideroblast formation remains elusive. Acquired sideroblastic anemia is usually observed in myelodysplastic syndrome. Because a subset of myelodysplastic syndrome harbors a somatic mutation of TET2, it may be involved in iron metabolism and/or heme biosynthesis in erythroblasts. (Kyoko Inokura, Tohru Fujiwara, Kei Saito, Tatsuya Iino, Shunsuke Hatta, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Kazuya Shimoda, Hideo Harigae) - 2017-02-03

 

Predictive value of pretransplantation molecular minimal residual disease assessment by WT1 gene expression in FLT3-positive acute myeloid leukemiaOpen in a New Window

The FMS-like tyrosine kinase 3 (FLT3) mutation in acute myeloid leukemia (AML) is a negative prognostic factor and, in these cases, allogeneic stem cell transplantation (allo-SCT) can represent an important therapeutic option, especially if performed in complete remission (CR). However, it is increasingly clear that not all cytological CRs (cCRs) are the same and that minimal residual disease (MRD) before allo-SCT could have an impact on AML outcome. Unfortunately, FLT3, due its instability of expression, is still not considered a good molecular MRD marker. (Anna Candoni, Federico De Marchi, Francesca Zanini, Maria Elena Zannier, Erica Simeone, Eleonora Toffoletti, Alexsia Chiarvesio, Michela Cerno, Carla Filì, Francesca Patriarca, Renato Fanin) - 2017-01-31

 

TEMPORARY REMOVAL: Use of ubiquitous, highly heterozygous copy number variants and digital droplet PCR to monitor chimerism after allogeneic haematopoietic stem cell transplantationOpen in a New Window

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the article will be reinstated.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. (John B. Whitlam, Ling Ling, Michael Swain, Tom Harrington, Oksana Mirochnik, Ian Brooks, Sara Cronin, Jackie Challis, Vida Petrovic, Damien L. Bruno, Francoise Mechinaud, Rachel Conyers, Howard Slater) - 2017-01-29

 

Androgen receptor expression in mantle cell lymphoma: Potential novel therapeutic implicationsOpen in a New Window

Mantle cell lymphoma (MCL) affects approximately 4500 patients/year in the US and demonstrates a male to female ratio of approximately 4:1. While the pathobiology underlying this ratio is unknown, the hematopoietic system is characterized by sex-related differences in androgen receptor (AR) expression, leading us to hypothesize that the male-biased incidence of MCL may reflect sex-related differences in AR signaling during MCL lymphomagenesis. To explore the AR axis in MCL, we evaluated AR expression in MCL cell lines and human tumors, and tested the impact of androgen pathway inhibition on MCL proliferation. (Elahe A. Mostaghel, Paul S. Martin, Stephen Mongovin, Shani Frayo, Ailin Zhang, Kerstin L. Edlefsen, Oliver W. Press, Ajay K. Gopal) - 2017-01-20

 

Analysis of parameters that affect human hematopoietic cell outputs in mutant c-kit-immunodeficient miceOpen in a New Window

Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34+ cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1–/–-IL2Rγc–/– (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdcscid/scid-IL2Rγc–/– (NSG) hosts. (Paul H. Miller, Gabrielle Rabu, Margarita MacAldaz, David J.H.F. Knapp, Alice M.S. Cheung, Kiran Dhillon, Naoto Nakamichi, Philip A. Beer, Leonard D. Shultz, R. Keith Humphries, Connie J. Eaves) - 2017-01-10

 

Polycomb complexes PRC1 and their function in hematopoiesisOpen in a New Window

Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated with reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repressive complexes (PRCs) endowed with distinct histone-tail-modifying activities. (Miguel Vidal, Katharzina Starowicz) - 2017-01-10

 

Induced pluripotent stem cell technology: A window for studying the pathogenesis of acquired aplastic anemia and possible applicationsOpen in a New Window

Recent progress in human induced pluripotent stem cells (iPSCs) has opened the door to a better understanding of the biology of human diseases, especially rare disorders such as acquired aplastic anemia, in which the target hematopoietic tissues are depleted. The advent of somatic cell reprogramming has presented new routes for generating hematopoietic stem cells from patient-derived iPSCs and their differentiation into hematopoietic lineages. The purpose of this review is to discuss the recent advances in iPSC research technology and their potential applications in disease modeling for understanding the pathogenesis of bone marrow failure syndrome and the potential clinical utility of iPSC-derived cells. (Mahmoud I. Elbadry, J. Luis Espinoza, Shinji Nakao) - 2017-01-03

 

Governing roles for Trib3 pseudokinase during stress erythropoiesisOpen in a New Window

In response to anemia, the heightened production of erythropoietin (EPO) can sharply promote erythroid progenitor cell (EPC) formation. Specific mediators of such EPO- accelerated erythropoiesis, however, are not well understood. Presently, we first report that the expression of Trib3 in adult bone marrow EPCs in vivo is nominal at steady state, but strongly activated on EPO challenge. In a knockout mouse model, Trib3 disruption modestly increased steady-state erythrocyte numbers and decreased mean corpuscular volume. (Arvind Dev, Ruth Asch, Edward Jachimowicz, Nicole Rainville, Ashley Johnson, Emily Greenfest-Allen, Don M. Wojchowski) - 2017-01-03

 

Hemangioblast, hemogenic endothelium, and primitive versus definitive hematopoiesisOpen in a New Window

The types of progenitors generated during the successive stages of embryonic blood development are now fairly well characterized. The terminology used to describe these waves, however, can still be confusing. What is truly primitive? What is uniquely definitive? These questions become even more challenging to answer when blood progenitors are derived in vitro upon the differentiation of embryonic stem cells or induced pluripotent stem cells. Similarly, the cellular origin of these blood progenitors can be controversial. (Georges Lacaud, Valerie Kouskoff) - 2016-12-31

 

Shipping mouse bone marrow: Keep it in the boneOpen in a New Window

Advances in sequencing technologies, animal modeling, gene editing, and bio-informatic analysis have provided researchers with a wider set of tools with which to address more complex scientific questions. This often requires diverse tools, skills, and expertise that are rarely all available in one group. As a result, collaborative research is essential and increasing, as demonstrated by the increase in co-authored papers [1]. (Ani E. Papazian, Youmna S. Kfoury, David T. Scadden) - 2016-12-31

 

Kinase signaling and targeted therapy for primary myelofibrosisOpen in a New Window

The myeloproliferative neoplasms (MPNs) are somatic mutation-driven hematologic malignancies characterized by bone marrow fibrosis and the accumulation of atypical megakaryocytes with reduced polyploidization in the primary myelofibrosis subtype of the MPNs. Increasing evidence points to a dominant role of abnormal megakaryocytes in disease initiation and progression. Here we review the literature related to kinase signaling pathways relevant to megakaryocyte differentiation and proliferation, including Aurora A kinase, RhoA/ROCK, and JAK/STAT, as well as the activities of their targeted inhibitors in models of the disease. (Qiong Yang, John D. Crispino, Qiang Jeremy Wen) - 2016-12-31

 

Letter to the Editor: Mutational analysis of hypermutation-related gene in acute leukemias and lymphomasOpen in a New Window

The POLE gene encodes the catalytic subunit of DNA polymerase ε (Polε), which is involved in DNA repair and chromosomal DNA replication [1]. The proofreading (exonuclease) function of Polε detects and removes misincorporated bases. Defects in this function due to POLE mutations may lead to a loss of replication fidelity and an increase in the mutational burden, resulting in tumor development. Germline mutations in POLE have been associated with colorectal cancer (CRC) predisposition [2]. Somatic mutations of POLE in the exonuclease domain are found in CRC and endometrial cancers that show association with hypermutability [3]. (Eun Ji Choi, Min Sung Kim, Nam Jin Yoo, Sug Hyung Lee) - 2016-12-26

 

Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effectOpen in a New Window

Allogeneic hematopoietic cell transplantation (allo-HCT) represents the only curative therapy for many haematological malignancies. Its curative potential is mostly attributed to the graft-versus-leukemia effect (GvL), which is mainly driven by donor T-cells. Donor lymphocyte infusions (DLI), likewise a second allo-HCT, have become a standard approach to treat AML and MDS relapses post allo-HCT. Although DLI have been used in this setting for decades, its effectivity and toxicity are still unpredictable in many patients. (Guillermo Orti, Pere Barba, Laura Fox, Olga Salamero, Francesc Bosch, David Valcarcel) - 2016-12-24

 

Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashionOpen in a New Window

There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. (Ahmad Samer Al-Homsi, Austin Goodyke, Kelli Cole, Marlee Muilenburg, Michael McLane, Sarah Abdel-Mageed, Yuxin Feng) - 2016-12-19

 

EphA5 and EphA7 forward signaling enhances human hematopoietic stem and progenitor cell maintenance, migration, and adhesion via Rac1 activationOpen in a New Window

The proliferation, differentiation, adhesion, and migration of hematopoietic stem and progenitor cells (HSPCs) are dependent upon bone marrow stromal cells (BMSCs). In this study, we found that human primitive HSPCs (CD34+CD38−), but not lineage-committed hematopoietic cell populations, express the tyrosine kinase receptors EphA5 and EphA7. Moreover, we found that the ephrinA5 ligand, the high-affinity binding partner of EphA5 and EphA7, is highly expressed by primary human BMSCs. Previous studies have reported that interactions between EphA and ephrinA play important roles in hematopoietic cell trafficking; however, their role in BMSC support of hematopoiesis had not been described previously. (Thao M. Nguyen, Agnieszka Arthur, Andrew C.W. Zannettino, Stan Gronthos) - 2016-12-14

 

The BAF45a/PHF10 subunit of SWI/SNF-like chromatin remodeling complexes is essential for hematopoietic stem cell maintenanceOpen in a New Window

The ability of hemopoietic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that establish and maintain stage-specific patterns of gene expression. However, the epigenetic factors responsible for mediating these regulatory events remain poorly defined. Here we provide evidence that BAF45a/PHF10, a subunit of SWI/SNF-like chromatin remodeling complexes, is essential for adult hemopoietic stem cell maintenance and myeloid lineage development. (Veneta Krasteva, Gerald R. Crabtree, Julie A. Lessard) - 2016-12-05

 

Impairment of fetal hematopoietic stem cell function in the absence ofOpen in a New Window

Fanconi anemia (FA) results from mutations in the genes necessary for DNA damage repair and often leads to progressive bone marrow failure. Although the exhaustion of the bone marrow leads to cytopenias in FA patients as they age, evidence from human FA and mouse model fetal livers suggests that hematopoietic defects originate in utero, which may lead to deficient seeding of the bone marrow. To address this possibility, we examined the consequences of loss of Fancd2, a central component of the FA pathway. (Sakiko Suzuki, Ronny R. Racine, Nathan A. Manalo, Sharon B. Cantor, Glen D. Raffel) - 2016-11-30

 

TEMPORARY REMOVAL: Assessment of hematopoietic and neurologic pathophysiology of -associated protein X-1 deficiency in a -knockout mouse modelOpen in a New Window

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. (Emanuele G. Coci, Nadine Thau-Habermann, Tobias Maetzig, Zhixiong Li, Christoph Klein, Susanne Petri, Axel Schambach) - 2014-10-28
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8/24/2017 » 8/27/2017
ISEH 46th Annual Meeting - Frankfurt, Germany

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