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Experimental Hematology InPress
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Variegated mutations in human cancersOpen in a New Window

RHOA is one of the most extensively investigated members of the Rho GTPase family of proteins and has long been implicated in malignant transformation as well as tumor invasion and metastasis. Recently, revolutionized sequencing platforms have revealed frequent RHOA mutations in a wide variety of human cancers, including angioimmunoblastic T-cell lymphoma, adult T-cell leukemia/lymphoma, germinal center B-cell lymphoma, diffuse-type gastric cancer, and other solid tumors. With their discrete positional distributions and types of amino acid substitution depending on cancer type, different RHOA mutations seem to have unique functional and biological properties. (Keisuke Kataoka, Seishi Ogawa) - 2016-09-29


Translating Leukemia Stem Cells into the Clinic: Harmonizing the HeterogeneityOpen in a New Window

Considerable evidence suggests that rare leukemia cells with stem cell features, including self-renewal capacity and drug resistance, are primarily responsible for both disease maintenance and relapses. Traditionally, these so-called leukemia stem cells (LSCs) have been identified in the laboratory by their ability to engraft acute myeloid leukemia (AML) into immunocompromised mice. For many years, only those rare AML cells characterized by a hematopoietic stem cell (HSC) CD34+CD38- phenotype were believed capable of generating leukemia in immunocompromised mice. (Breann Yanagisawa, Gabriel Ghiaur, B. Douglas Smith, Richard J. Jones) - 2016-09-28


Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukaemia clonesOpen in a New Window

Chronic lymphocytic leukaemia (CLL) is characterised by the accumulation of clonally-derived mature CD5high B-cells, however the cellular origin of CLL is still unknown. Patients with CLL also harbour variable numbers of CD5low B-cells, but the clonal relationship of these cells to the bulk disease is unknown and can have important implications for monitoring, treating and understanding the biology of CLL. Here we use B-cell receptors (BCRs) as molecular barcodes to first show that the great majority of CD5low B-cells in the blood of CLL patients are clonally related to CD5high CLL B-cells by single-cell BCR sequencing. (Rachael J.M. Bashford-Rogers, Anne L. Palser, Clare Hodkinson, Joanna Baxter, George A. Follows, George S. Vassiliou, Paul Kellam) - 2016-09-27


Alterations in bone marrow microenvironment may elicit defective hematopoiesis: a comparison of aplastic anemia, chronic myeloid leukemia and normal bone marrowOpen in a New Window

Hematopoiesis involves complex interactions between hematopoietic cells and the bone marrow (BM) microenvironment; the specific causes and mechanisms underlying dysregulated hematopoiesis are unknown. Here, BM biopsy specimens from patients with aplastic anemia (AA), chronic myeloid leukemia (CML), and normal marrow were analyzed by semiquantitative immunohistochemistry to determine changes in the hematopoietic stem cell (HSC) compartment and BM microenvironment.HSC levels were lowest in AA and highest in CML. (Meerim Park, Chan-Jeoung Park, Young Wook Cho, Seongsoo Jang, Jung-Hee Lee, Je-Hwan Lee, Kyoo-Hyung Lee, Young Ho Lee) - 2016-09-27


Clinical grade regulatory T cells: comparative analysis of large-scale expansion conditionsOpen in a New Window

Recent clinical trials have shown the high potential of regulatory T cells (Tregs) in prevention of acute and chronic graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation but immune interventions require high Treg cell numbers. With respect to limited natural occurrence, development and optimization of large-scale expansion protocols of clinical-grade Tregs are essential if considered for therapeutic use. (Sarvari Velaga, Christina Alter, Ulrike Dringenberg, Christina T. Thiesler, Sandra Kuhs, Sven Olek, Sya N. Ukena, Anke Franzke) - 2016-09-27


Proinflammatory signals are insufficient to drive definitive hematopoietic specification of human HSCs in vitroOpen in a New Window

Recent studies in zebrafish and mice demonstrated that proinflammatory signaling is a positive regulator of definitive hematopoietic development. Whether proinflammatory signaling regulates also human hematopoietic specification remains unknown. Here, we explored the impact of the proinflammatory cytokines tumor necrosis factor-α (TNFα), interferon-γ (IFNγ) and interleukin-1β (IL1β) on in vitro hematopoietic differentiation using human pluripotent stem cells (hPSCs). Gene expression analysis and ELISA revealed the absence of a proinflammatory signature during hematopoietic development of hPSCs. (Alessandra Giorgetti, Julio Castaño, Clara Bueno, Rafael Diaz de la Guardia, Mario Delgado, Anna Bigas, Lluis Espinosa, Pablo Menendez) - 2016-09-27


AC220 and AraC cause differential inhibitory dynamic of patient derived M5-AML with FLT3-ITD, and thus ultimate distinct therapeutic outcomesOpen in a New Window

Engrafting a M5-AML patient bone marrow (BM) cells into immunocompromised mice (AM7577) achieved serially transferrable stable AML and eventual mortality. The disease starts at BM followed by expansion to peripherals, typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in mice have similar myeloid morphology, phenotypes and genotypes (including FLT3-ITD) as the original patient. Autocrine mechanisms of human GM-CSF/IL-3 likely support AM7577 growth in mice. (Xiaoyu An, Jinping Liu, Na Wang, Di Wang, Liang Huang, Likun Zhang, Jie Cai, Jean-Pierre Wery, Demin Zhou, Jianfeng Zhou, Qi-Xiang Li) - 2016-09-23


The AMP-activated protein kinase beta 1 subunit modulates erythrocyte integrityOpen in a New Window

(Emma L. Cambridge, Zoe McIntyre, Simon Clare, Mark J. Arends, David Goulding, Christopher Isherwood, Susana S. Caetano, Carmen Ballesteros Reviriego, Agnieszka Swiatkowska, Leanne Kane, Katherine Harcourt, The Sanger Mouse Genetics Project, David J. Adams, Jacqueline K. White, Anneliese O. Speak) - 2016-09-22


NOX-driven ROS formation in cell transformation of FLT3-ITD positive AMLOpen in a New Window

In different types of myeloid leukemia, increased formation of reactive oxygen species (ROS) has been noted and associated with aspects of cell transformation including the promotion of leukemic cell proliferation and migration, as well as DNA-damage and accumulation of mutations. Work reviewed in this article has shown the involvement of NADPH oxidase (NOX)-derived ROS downstream of oncogenic protein-tyrosine kinases in both processes, and the related pathways have been partially identified. FLT3-ITD, an important oncoprotein in a subset of AML, causes activation of AKT and subsequently stabilization of p22phox, a regulatory subunit for NOX1-4. (Ashok Kumar Jayavelu, Jennifer N. Moloney, Frank-D. Böhmer, Thomas G. Cotter) - 2016-09-22


Constitutive Kit activity triggers B cell acute lymphoblastic leukemia-like disease in miceOpen in a New Window

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and is of pro- or pre-B cell origin in most cases. The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B lineage origin. (Robin R. Weidemann, Rayk Behrendt, Kristina B. Schoedel, Werner Müller, Axel Roers, Alexander Gerbaulet) - 2016-09-21


Pharmacological inhibition of AKT activity in human CD34 cells enhances their ability to engraft immunodeficient miceOpen in a New Window

Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand functional HSCs ex vivo. To determine the role of PI3K/AKT signaling in human hematopoietic stem and progenitor cell (HSPC) maintenance, we examined the effect of genetic and pharmacological inhibition of AKT on human cord blood CD34+ cells. We found that knockdown of AKT1 in human cord blood CD34+ cells using siRNAs targeting AKT1 enhances their quiescence and colony formation potential in vitro. (Sisi Chen, Rui Gao, Michihiro Kobayashi, Hao Yu, Chonghua Yao, Reuben Kapur, Mervin C. Yoder, Yan Liu) - 2016-09-16


MicroRNA-155 is upregulated in MLL-rearranged AML but its absence does not affect leukemia developmentOpen in a New Window

MicroRNA-155 (miR-155) is an oncogenic miRNA upregulated in various tumor types and leukemias and has been suggested as a potential drug target. Based on our previous work detecting high miR-155 levels in response to Meis1 overexpression in a murine Hox leukemia model, we show here the relationship among HOXA9, MEIS1, and miR-155 levels in MLL-translocated acute myeloid leukemia (AML) patients. Using mouse bone marrow cells transformed by MLL-fusion genes expressing graduated levels of Meis1, we show a positive correlation between miR-155 and Meis1. (Edith Schneider, Anna Staffas, Linda Röhner, Kathrin Krowiorz, Michael Heuser, Konstanze Döhner, Lars Bullinger, Hartmut Döhner, Linda Fogelstrand, Arefeh Rouhi, Florian Kuchenbauer, Lars Palmqvist) - 2016-09-09


Sustained enhancement of OCTN1 transporter expression in association with hydroxyurea induced γ-globin expression in erythroid progenitorsOpen in a New Window

The clinical benefits of hydroxyurea (HU) treatment in patients with sickle cell disease (SCD) are due largely to increased γ-globin expression. However, mechanisms that control γ-globin expression by HU in erythroid progenitors are incompletely understood. Here, we investigated the role of two HU transporters, urea transporter B (UTB) and organic cation/carnitine transporter 1 (OCTN1), in this process. Endogenous expression of both transporters peaked toward the end of erythroid differentiation. (Aisha L. Walker, Solomon Ofori-Acquah) - 2016-09-08


Loss of ASXL1 triggers an apoptotic response in human hematopoietic stem and progenitor cellsOpen in a New Window

ASXL1 is frequently mutated in myelodysplastic syndrome and other hematological malignancies. It has been reported that a loss of ASXL1 leads to a reduction of H3K27me3 via the polycomb repressive complex 2 (PRC2). To determine the role of ASXL1 loss in normal hematopoietic stem and progenitor cells, cord blood CD34+ cells were transduced with independent small hairpin interfering RNA lentiviral vectors against ASXL1 and cultured under myeloid and erythroid permissive conditions. Knockdown of ASXL1 led to a significant reduction in stem-cell frequency and a reduced cell expansion along the myeloid lineage. (Susan Hilgendorf, Hendrik Folkerts, Jan Jacob Schuringa, Edo Vellenga) - 2016-09-08


Primary Cilia are Present on Human Blood and Bone Marrow Cells and Mediate Hedgehog SignalingOpen in a New Window

Primary cilia are non-motile microtubule-based organelles that are present on the cellular membrane of all eukaryotic cells. Functional cilia are required for the response to developmental signaling pathways such as Hedgehog (Hh) and Wnt/β-catenin. Although the Hh pathway has been shown to be active in leukemia and other blood cancers, there have been no reports describing the presence of primary cilia in human blood or leukemia cells. In the present study, we show that nearly all human blood and bone marrow cells have primary cilia (97-99%). (Mohan Singh, Parvesh Chaudhry, Akil A. Merchant) - 2016-09-06


Preclinical rationale for TGF-β inhibition as a therapeutic target for the treatment of myelofibrosisOpen in a New Window

To assess the role of abnormal transforming growth factor-beta (TGF-β) signaling in the pathogenesis of primary myelofibrosis (PMF), the effects of the TGF-β receptor-1 kinase inhibitor SB431542 on ex vivo expansion of hematopoietic cells in cultures from patients with JAK2V617+-polycythemia vera (PV) or PMF (JAK2V617F+, CALRpQ365f+, or unknown) and from normal sources (adult blood, AB, or cord blood, CB) were compared. In cultures of normal sources, SB431542 significantly increased by 2.5-fold the number of progenitor cells generated by days 1–2 (CD34+) and 6 (colony-forming cells) (CB) and that of precursor cells, mostly immature erythroblasts, by days 14–17 (AB and CB). (Ilaria Ceglia, Amylou C. Dueck, Francesca Masiello, Fabrizio Martelli, Wu He, Giulia Federici, Emanuel F. Petricoin, Ann Zeuner, Camelia Iancu-Rubin, Rona Weinberg, Ronald Hoffman, John Mascarenhas, Anna Rita Migliaccio) - 2016-08-31


Mechanisms of heparanase inhibitors in cancer therapyOpen in a New Window

Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains contributing to breakdown of the extracellular matrix. Increased expression of heparanase has been observed in numerous malignancies and is associated with a poor prognosis. It has generated significant interest as a potential antineoplastic target because of the multiple roles it plays in tumor growth and metastasis. The protumorigenic effects of heparanase are enhanced by the release of heparan sulfate side chains, with subsequent increase in bioactive fragments and cytokine levels, both of which promote tumor invasion, angiogenesis, and metastasis. (Benjamin Heyman, Yiping Yang) - 2016-08-27


Metformin inhibits JAK2V617F activity in MPN cells by activating AMPK and PP2A complexes containing the B56α subunitOpen in a New Window

Metformin suppresses the growth of a variety of malignant hematologic cells. It is widely accepted that metformin inhibits the growth of malignant cells primarily by suppressing the mTOR pathway or regulating autophagy. In contrast, we found another possible mechanism that inhibits the growth of malignant cells, suppression of the activity of the oncogenic kinase JAK2V617F. We identified at least two distinct mechanisms involved in metformin-induced JAK2V617F inhibition. First, metformin increases reactive oxygen species levels in these cells, leading to the inhibition of SHP-2, a positive regulator of JAK2V617F. (Ichiro Kawashima, Keita Kirito) - 2016-08-27


Delivery of RNA-based molecules to human hematopoietic stem and progenitor cells for modulation of gene expressionOpen in a New Window

Gene modulation of human hematopoietic stem and progenitor cells (HSPCs) harbors great potential for therapeutic application of these cells and presents a versatile tool in basic research to enhance our understanding of HSPC biology. However, stable genetic modification might be adverse, particularly in clinical settings. Here, we review a broad range of approaches to transient, nonviral modulation of protein expression with a focus on RNA-based methods. We compare different delivery methods and describe the usefulness of RNA molecules for overexpression as well as downregulation of proteins in HSPCs. (Yvonne Diener, Andreas Bosio, Ute Bissels) - 2016-08-27


Uncoupling protein 2 deficiency results in higher neutrophil counts and lower B-cell counts during aging in miceOpen in a New Window

Progress of age-related hematopoietic diseases such as myelodysplastic syndrome has previously been linked to enhanced levels of reactive oxygen species (ROS). Uncoupling protein 2 (UCP2) was found to reduce mitochondrial ROS production through uncoupling of the respiratory chain. The impact of UCP2 loss and elevated ROS on hematopoiesis during aging has not yet been investigated. In this study, UCP2 knockout mice were analyzed at aging stages of 3, 12, and 24 months with respect to oxidative and energy status of bone marrow cells. (Christin Kretzschmar, Catrin Roolf, Katrin Timmer, Anett Sekora, Gudrun Knübel, Hugo Murua Escobar, Robert Jaster, Sarah Müller, Georg Fuellen, Rüdiger Köhling, Christian Junghanss) - 2016-08-18


Quantitative proteomic analysis and comparison of two bone marrow stromal cell lines using the SILAC methodOpen in a New Window

Two human bone marrow stromal cell lines, HS5 and HS27a, co-cultured with myeloid cells, have frequently been used in studies of cross talk between cells in the bone marrow microenvironment and hematopoietic cells. Altered expression of proteins is typically associated with cell–cell signal transduction and regulation of cellular functions. Many studies have focused on key proteins that contribute to functional differences in cell co-culture models, but global quantitative proteome analysis of HS5 and HS27a has not been performed. (Xiang Li, Ting Wan, Sijie Zhang, Dongliang Li, Xiaofeng Han) - 2016-08-15


Immunological properties of bone marrow microenvironment 1 year after allogeneic hematopoietic stem cell transplantationOpen in a New Window

Regeneration of the bone marrow microenvironment after transplantation of allogeneic hematopoietic stem cells is poorly explored. The goal of our study was to investigate this process focusing on immunologic factors: concentrations of selected cytokines, expression of immunosuppressive proteins CD47 and CD274 on hematopoietic stem cells, and frequency of T regulatory lymphocytes (Tregs). Bone marrow samples were collected before transplantation, on the day of transplantation, and at the 1-year follow-up. (Agnieszka Ciomber, Iwona Mitrus, Wojciech Fidyk, Andrzej Smagur, Agata Chwieduk, Magdalena Glowala-Kosinska, Tomasz Czerw, Małgorzata Sobczyk-Kruszelnicka, Włodzimierz Mendrek, Maria Sadus-Wojciechowska, Jacek Najda, Jerzy Holowiecki, Sebastian Giebel) - 2016-08-11


Precision in donor selection: Identifying ideal stem-cell donors through their T cellsOpen in a New Window

HLA-identical siblings have always been considered ideal donors for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of hematologic cancers. Recent data suggest that we should rethink this paradigm. In “High Graft CD8+ Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning,” we identified a group of stem-cell donors whose grafts contain an optimal composition of T-cells, leading to a dramatic decrease in disease relapse risk and an improvement in overall survival following allo-HSCT. (Adam Widman, Ran Reshef) - 2016-08-02


Complement cascade gene expression defines novel prognostic subgroups of acute myeloid leukemiaOpen in a New Window

The involvement of the complement pathway in cancer is supported by a growing body of evidence, and yet its role in acute myeloid leukemia (AML) has not been extensively studied. We examined the expression of 87 genes in the complement, coagulation, and fibrinolysis-proteolytic pathways in 374 cytogenetically normal AML samples and observed that these samples can be divided into subgroups on the basis of complement gene expression. Three complement regulatory genes were linked to poor outcome as individual factors in a multivariate analysis (CFH, CFD, and SERPING1) in multiple cohorts. (Isabelle Laverdière, Meaghan Boileau, Tobias Herold, Janusz Rak, Wolfgang E. Berdel, Bernhard Wörmann, Wolfgang Hiddemann, Karsten Spiekermann, Stefan K. Bohlander, Kolja Eppert) - 2016-07-27


Improving the safety of T-Cell therapies using an inducible caspase-9 geneOpen in a New Window

Adoptive transfer of T cells can be an effective anticancer treatment. However, uncontrolled or unpredictable immediate or persistent toxic effects are a source of concern. The ability to conditionally eliminate aberrant cells in vivo is therefore becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human T cells without impairing phenotype, function, or antigen specificity. (Xiaoou Zhou, Malcolm K. Brenner) - 2016-07-27


JAK2 V617F stimulates proliferation of erythropoietin-dependent erythroid progenitors and delays their differentiation by activating Stat1 and other nonerythroid signaling pathwaysOpen in a New Window

JAK2 V617F is a mutant-activated JAK2 kinase found in most polycythemia vera (PV) patients; it skews normal proliferation and differentiation of hematopoietic stem and progenitor cells and simulates aberrant expansion of erythroid progenitors. JAK2 V617F is known to activate some signaling pathways not normally activated in mature erythroblasts, but there has been no systematic study of signal transduction pathways or gene expression in erythroid cells expressing JAK2 V617F undergoing erythropoietin (Epo)-dependent terminal differentiation. (Jiahai Shi, Bingbing Yuan, Wenqian Hu, Harvey Lodish) - 2016-07-27


Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations inOpen in a New Window

Epigenetic alteration may play a role in age-associated dysfunction of stem cells and predispose to the development of hematological cancers. We analyzed global levels of hematopoietic 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in a cross-sectional study comprising 198 unrelated individuals from four age categories (neonates, 25–30, 70–75, and >90 years old) by liquid chromatography-electrospray ionization-tandem mass spectrometry with multiple reaction monitoring. X-chromosome inactivation (XCI) ratios and telomere length (TL) were measured in all individuals by polymerase chain reaction. (Manuel Buscarlet, Alain Tessier, Sylvie Provost, Luigina Mollica, Lambert Busque) - 2016-07-27


Longitudinal analyses of leukemia-associated antigen-specific CD8 T cells in patients after allogeneic stem cell transplantationOpen in a New Window

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GVL) effects, which are exerted by donor T cells directed against leukemic-associated antigens (LAAs), are considered to play a crucial role in disease eradication. Although the expansion of cytotoxic T lymphocytes (CTLs) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data on CTLs mediating GVL effects are limited. (Elke Rücker-Braun, Cornelia S. Link, Maria Schmiedgen, Antje Tunger, Petra Vizjak, Raphael Teipel, Rebekka Wehner, Denise Kühn, Yannik F. Fuchs, Uta Oelschlägel, Lothar Germeroth, Marc Schmitz, Martin Bornhäuser, Johannes Schetelig, Falk Heidenreich) - 2016-07-27


Tunneling nanotubes mediate the transfer of stem cell marker CD133 between hematopoietic progenitor cellsOpen in a New Window

Deciphering all mechanisms of intercellular communication used by hematopoietic progenitors is important, not only for basic stem cell research, but also in view of their therapeutic relevance. Here, we investigated whether these cells can produce the thin F-actin-based plasma membrane protrusions referred to as tunneling nanotubes (TNTs), which are known to bridge cells over long distances without contact with the substratum and transfer cargo molecules along them in various biological processes. (Doreen Reichert, Julia Scheinpflug, Jana Karbanová, Daniel Freund, Martin Bornhäuser, Denis Corbeil) - 2016-07-27


A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromesOpen in a New Window

Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. (Fabrice Danjou, Claudio Fozza, Magdalena Zoledziewska, Antonella Mulas, Giovanna Corda, Salvatore Contini, Fausto Dore, Antonio Galleu, Anna Angela Di Tucci, Giovanni Caocci, Eleonora Gaviano, Giancarlo Latte, Attilio Gabbas, Paolo Casula, Lucia Gemma Delogu, Giorgio La Nasa, Emanuele Angelucci, Francesco Cucca, Maurizio Longinotti) - 2016-07-20


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 (Emanuele G. Coci, Nadine Thau-Habermann, Tobias Maetzig, Zhixiong Li, Christoph Klein, Susanne Petri, Axel Schambach) - 2014-10-28
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