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Experimental Hematology InPress
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Granulocyte Colony Stimulating Factor Receptor (G-CSFR) signaling in severe congenital neutropenia, chronic neutrophilic leukemia and related malignanciesOpen in a New Window

Granulocyte colony stimulating factor (G-CSF) is a hematopoietic cytokine that stimulates neutrophil production and hematopoietic stem cell mobilization by initiating the dimerization of homodimeric granulocyte colony stimulating factor receptor (G-CSFR). Different mutations of CSF3R have been linked to a unique spectrum of myeloid disorders and related malignancies. Myeloid disorders caused by the CSF3R mutations include severe congenital neutropenia (SCN), chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). (Pankaj Dwivedi, Kenneth D. Greis) - 2016-10-24


MOZ and BMI1 act synergistically to maintain Hematopoietic Stem CellsOpen in a New Window

Chromatin plays a central role in maintaining hematopoietic stem cells and during their stepwise differentiation. While a large number of histone modifications and chromatin modifying enzymes have been identified, how these act in concert to produce specific phenotypic outcomes remains to be established. MOZ (KAT6A) is a lysine acetyltransferase and enhances transcription at target gene loci. In contrast, the polycomb group protein BMI1 (PCGF4) is part of the transcriptionally repressive PRC1 complex. (Bilal N. Sheikh, Donald Metcalf, Anne K. Voss, Tim Thomas) - 2016-10-20


Everolimus restrains the IL-17A-dependent osteoclast-like transdifferentiation of dendritic cells in multiple myelomaOpen in a New Window

Interleukin-17A (IL-17A) promotes the osteoclast (OC)-like differentiation of dendritic cells (DCs) in multiple myeloma (MM), and contributes to the pathogenesis of myeloma bone disease (MBD). In our study, EVR significantly abrogated the in vitro OC-like activity of DCs from 12 MM patients. Exploring the EVR effects, we found that the inhibition of the osteo-erosive activity of OC-DCs was mostly due to the blockade of signals driven by the IL-17A receptor toward CEBPbeta/MAFB axis Therefore, MM patients with MBD would probably benefit from mTOR inhibition. (Marco Tucci, Stefania Stucci, Anna Passarelli, Stella D’Oronzo, Franco Silvestris) - 2016-10-17


Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapyOpen in a New Window

NK cells play a significant role in reducing relapse in patients with hematological malignancies following allogeneic stem cell transplantation but NK cell number and naturally occurring inhibitory signals limit their capability. IL-15 and 4-1BBL are important modulators of NK expansion and functional activation. With an aim to overcome these limitations, cord blood (CB) mononuclear cells (MNC) were ex-vivo expanded (EvE) for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wildtype K562 (WTK562). (Janet Ayello, Jessica Hochberg, Allyson Flower, Yaya Chu, Laxmi V. Baxi, William Quish, Carmella van de Ven, Mitchell S. Cairo) - 2016-10-17


HIF1α-induced PDGFRβ signaling promotes developmental HSC production via IL-6 activationOpen in a New Window

Hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate into all the mature blood cell lineages and thereby reconstitute the entire blood system. As such, HSCs are therapeutically valuable for treatment of hematological malignances and bone marrow failure. We recently showed that transient glucose elevation elicited dose-dependent effects on HSCs through elevated metabolic activity and subsequent ROS-mediated induction of Hypoxia Inducible Factor 1α (Hif1α). Platelet Derived Growth Factor B (pdgfb), a Hif1α-target, and its receptor, pdgfrb, were significantly upregulated in response to metabolic stimulation. (Sung-Eun Lim, Virginie Esain, Wanda Kwan, Lindsay N. Theodore, Mauricio Cortes, Isaura M. Frost, Sarah Y. Liu, Trista E. North) - 2016-10-14


Csk-binding protein controls red blood cell development via regulation of Lyn tyrosine kinase activityOpen in a New Window

(Janice H.C. Plani-Lam, Neli S. Slavova-Azmanova, Nicole Kucera, Alison Louw, Jiulia Satiaputra, Peter Singer, Kong-Peng Lam, Margaret L. Hibbs, Evan Ingley) - 2016-10-14


AML1-ETO promotes SIRT1 expression to enhance leukemogenesis of t(8;21) acute myeloid leukemiaOpen in a New Window

SIRT1 has been recently found to play an important role in a variety of solid and hematologic malignancies. The expression and function of SIRT1 may be completely different depending on cell type and gene subtype and it can act as a tumor suppressor or oncogene. In this study, we show that SIRT1 mRNA and protein levels are overexpressed in t(8;21) AML cells. AML1-ETO triggers the activation of SIRT1 by binding at AML1-binding sites on SIRT1 promoter. Pharmacologic targeting or RNAi-mediated inhibition of SIRT1 induce G1 arrest, apoptosis, and proliferation inhibition that is more sensitive in AML1-ETO positive cell lines than the negative. (Lei Zhou, Qian Wang, Xiaosu Chen, Lin Fu, Xiaodong Zhang, Lijun Wang, Ailing Deng, Dandan Li, Jing Liu, Na Lv, Lili Wang, Yonghui Li, Daihong Liu, Li Yu, Liping Dou) - 2016-10-07


Using zebrafish models of leukemia to streamline drug screening and discoveryOpen in a New Window

Current treatment strategies for acute leukemias largely rely on nonspecific cytotoxic drugs that result in high therapy-related morbidity and mortality. Cost effective, pertinent animal models are needed to link in vitro studies with the development of new therapeutic agents in clinical trials on a high-throughput scale. However, targeted therapies have had limited success moving from bench-to-clinic, often due to unexpected off-target effects. The zebrafish has emerged as a reliable in vivo tool for modeling human leukemia. (Adam P. Deveau, Victoria L. Bentley, Jason N. Berman) - 2016-10-06


MiR-17-92 represses PTPROt and PP2A phosphatases and amplifies tonic BCR signaling in DLBCL cellsOpen in a New Window

B-cell receptor (BCR) signaling plays pivotal role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL), and targeting the BCR pathway is a highly promising therapeutic strategy in this malignancy. Oncogenic microRNA miR-17-92 modulates multiple cellular processes such as survival, proliferation, apoptosis, angiogenesis and BCR signaling. In the present study, we identified new targets of miR-17-92, PTPROt and PP2A phosphatases, which regulate SYK and AKT activity- critical components of BCR signal transduction in DLBCL cells. (Ewa Jablonska, Patryk Gorniak, Maciej Szydlowski, Tomasz Sewastianik, Emilia Bialopiotrowicz, Anna Polak, Krzysztof Warzocha, Przemyslaw Juszczynski) - 2016-10-06


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 angio-immunoblastic 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 clinical setting: 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 the 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) and chronic myeloid leukemia (CML) and from healthy controls 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 indicated the high potential of regulatory T cells (Tregs) in the prevention of acute and chronic graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation, but immune interventions require large numbers of Tregs. With respect to their limited natural occurrence, development and optimization of protocols for large-scale expansion of clinical-grade Tregs are essential if considered for therapeutic use. We compared different clinical-grade large-scale expansion protocols for repetitive transfer of large numbers of Tregs in clinical trials for the prevention of acute and/or chronic GvHD. (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 have revealed that proinflammatory signaling is a positive regulator of definitive hematopoietic development. Whether proinflammatory signaling also regulates 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. Gene expression analysis and enzyme-linked immunosorbent assay revealed the absence of a proinflammatory signature during hematopoietic development of human pluripotent stem cells. (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 in patient-derived M5-AML with FLT3-ITD and, thus, ultimate distinct therapeutic outcomesOpen in a New Window

Engrafting the bone marrow cells of patient with M5 acute myeloid leukemia into immunocompromised mice (AM7577) resulted in serially transferrable stable AML and eventual mortality. The disease starts in the bone marrow and then expands to peripheral areas, which is typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in the mice had myeloid morphology, phenotypes, and genotypes (including the internal tandem duplication of FMS-like tyrosine kinase receptor 3 gene [FLT3-ITD]) similar to those of the original patient. (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

Failure to maintain a normal in vivo erythrocyte half-life results in the development of hemolytic anemia. Half-life is affected by numerous factors, including energy balance, electrolyte gradients, reactive oxygen species, and membrane plasticity. The heterotrimeric AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that acts as a critical regulator of cellular energy balance. Previous roles for the alpha 1 and gamma 1 subunits in the control of erythrocyte survival have been reported. (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 revealed 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. (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, in most cases, is of pro- or pre-B cell origin (B-ALL). 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) transplantation remains limited by the inability to expand functional HSCs ex vivo. To determine the role of phosphoinositide 3-kinase (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 umbilical cord blood (UCB) CD34+ cells. We found that knock-down of AKT1 in human UCB CD34+ cells using short interfering RNAs 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 nonmotile, 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


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


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


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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