DOCSLIB.ORG

A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates the Adaptation of BRAF-Mutated Melanoma to MAPK Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates the Adaptation of BRAF-Mutated Melanoma to MAPK Inhibitors Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0253 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A fatty acid oxidation-dependent metabolic shift regulates the adaptation of BRAF- mutated melanoma to MAPK inhibitors Andrea Aloia1,*, Daniela Müllhaupt1, Christophe D. Chabbert1, £, Tanja Eberhart1, Stefanie Flückiger- Mangual1, Ana Vukolic1, Ossia Eichhoff2, Anja Irmisch2, Leila T. Alexander3, §, Ernesto Scibona4, Dennie T. Frederick5, Benchun Miao5, Tian Tian6, Chaoran Cheng6, Lawrence N. Kwong7, Zhi Wei6, Ryan J. Sullivan5, Genevieve M. Boland8, Meenhard Herlyn9, Keith T. Flaherty5, Nicola Zamboni3, Reinhard Dummer2, Gao Zhang9, #, Mitchell P. Levesque2, $, Wilhelm Krek1, †, Werner J. Kovacs1, 10, $, * 1ETH Zurich, Institute of Molecular Health Sciences, 8093 Zurich, Switzerland 2University Hospital Zurich, Department of Dermatology, 8091 Zurich, Switzerland 3ETH Zurich, Institute of Molecular System Biology, 8093 Zurich, Switzerland 4ETH Zurich, Institute of Chemical and Bioengineering, 8093 Zurich, Switzerland 5Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA 6Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USA 7Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 770303, USA 8Department of Surgery, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA 9Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA 10Lead Contact $Co-senior authors £Current address: Roche Innovation Center Zurich, 8952 Schlieren, Switzerland §Current address: SIB Swiss Institute of Bioinformatics, Personalized Health Informatics, 4056 Basel, Switzerland #Current address: Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, and Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA †Deceased 29. August 2018 1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0253 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. *Correspondence to: Werner Kovacs, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern- Weg 7, HPL H16.1, CH-8093 Zurich, Switzerland. Tel.: +41 44 633 3084. E-mail: [email protected] *Correspondence to: Andrea Aloia, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern- Weg 7, HPL H23.2, CH-8093 Zurich, Switzerland. Tel.: +41 44 633 3360. E-mail: [email protected] Running title MAPKi induce fatty acid oxidation in BRAFV600E melanomas Keywords BRAF-mutated melanoma, adaptive drug resistance, fatty acid oxidation, CD36, MAPK inhibitors 2 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0253 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: Treatment of BRAFV600E-mutant melanomas with mitogen-activated protein kinase inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand non-mutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi. Experimental Design: By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients’ pre- and on-treatment tumor specimens. Results: Melanoma cells treated with MAPKi displayed increased levels of CD36 and of peroxisome proliferator-activated receptor (PPAR)-mediated and carnitine palmitoyltransferase 1A (CPT1A)- dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E-mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis and MAPK synergistically inhibits tumor cell growth in vitro and in vivo. Conclusions: Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E-mutant melanoma. 3 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0253 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance Transiently resistant cells adapting to mitogen-activated protein kinase inhibitors (MAPKi) are responsible for acquired drug resistance. We identified CD36 as a marker of transiently resistant and MAPKi-tolerant BRAFV600E melanoma cells. In addition, we describe an early metabolic reprogramming mechanism induced by MAPKi through increased FAO which is required to survive MAPKi-induced metabolic stress prior to acquiring drug resistance. FAO inhibitors increase the glycolytic flux in untreated and MAPKi-treated melanoma cells as a compensatory mechanism to FAO inhibition. To exploit melanoma cells’ metabolic plasticity for therapeutic intervention, we propose a triple combination of MAPK, FAO and glycolytic inhibitors as a novel treatment option to prevent drug resistance in BRAF-mutated melanomas. DECLARATION OF INTEREST CDC is a full-time employee of Roche AG and a shareholder in AstraZeneca. Other authors declare no competing interests. 4 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0253 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Malignant melanoma is an aggressive skin tumor with poor prognosis due to metastasis and therapeutic resistance (1). Approximately 50% of melanoma patients carry gain-of-function mutations in the BRAF gene (2). The most frequent mutation is the substitution of valine at position 600 by glutamic acid (BRAFV600E) resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) signal transduction pathway (3). BRAF plays a pivotal role in the MAPK pathway by promoting cell division, proliferation, and survival (4). Since BRAF is a critical mediator of melanomagenesis, BRAFV600E inhibitors (BRAFi) and MEK/ERK kinase inhibitors (MEKi) were developed to target key components of the MAPK signaling pathway and induce cell death (5,6). BRAFi alone or in combination with MEKi have shown clinical efficacy in BRAF-mutated metastatic melanoma patients (7,8). However, drug resistance inevitably develops and most patients relapse within a few months with limited benefits. Drug resistance represents a common complication of targeted therapies hampering long-term treatment success (9). To date, numerous mechanisms of acquired drug resistance have already been identified in metastatic melanoma patients (10). Mechanisms of therapy resistance are quite heterogeneous because they can be different among patients (inter-patient heterogeneity), co-exist in tumors of the same patient (intra-patient heterogeneity), and be identified within a single tumor (intra-tumor heterogeneity) (11). Resistance can be classified as pre-existing in cells that are insensitive to treatments (primary or intrinsic resistance), as acquired when progressive disease occurs after clinical benefits (secondary or acquired resistance) or as initial attenuation of therapeutic interventions preceding acquired resistance (adaptive resistance). When MAPKi-treated melanoma cells develop adaptive resistance, they become transiently resistant by modifying their molecular phenotype through non-genetic mechanisms such as phenotype switching or metabolic reprogramming (12). Continuous drug treatment drives transiently resistant cells into a stable drug-tolerant state (13). Phenotype switching is the transition from a proliferative (epithelial-like) state to an invasive (mesenchymal-like) one which has been described as a characteristic feature of drug-tolerant melanoma cells and linked to increased resistance to MAPKi (14). Metabolic reprogramming is an essential aspect in the emergence of the drug-tolerant state, in particular as MAPK inhibition reduces glycolysis (15), induces oxidative phosphorylation (OXPHOS) (16,17), and triggers the expression of a mitochondrial biogenesis gene signature (18). Mitochondria are the location of essential energy producing 5 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0253 Author manuscripts have
Load more

Recommended publications
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • Role of C5ar1 and C5L2 Receptors in Ischemia-Reperfusion Injury
    Journal of Clinical Medicine Article Role of C5aR1 and C5L2 Receptors in Ischemia-Reperfusion Injury Carlos Arias-Cabrales 1,* , Eva Rodriguez-Garcia 1, Javier Gimeno 2, David Benito 3, María José Pérez-Sáez 1, Dolores Redondo-Pachón 1, Anna Buxeda 1, Carla Burballa 1, Marta Crespo 1, Marta Riera 3,* and Julio Pascual 1,* 1 Department of Nephrology, Parc de Salut Mar, 08003 Barcelona, Spain; [email protected] (E.R.-G.); [email protected] (M.J.P.-S.); [email protected] (D.R.-P.); [email protected] (A.B.); [email protected] (C.B.); [email protected] (M.C.) 2 Department of Pathology, Parc de Salut Mar, 08003 Barcelona, Spain; [email protected] 3 Kidney Research Group, Hospital del Mar Medical Research Institute, IMIM, 08003 Barcelona, Spain; [email protected] * Correspondence: [email protected] (C.A.-C.); [email protected] (M.R.); [email protected] (J.P.) Abstract: The role of C5a receptors (C5aR1 and C5L2) in renal ischemia-reperfusion injury (IRI) is uncertain. We generated an in vitro model of hypoxia/reoxygenation with human proximal tubule epithelial cells to mimic some IRI events. C5aR1, membrane attack complex (MAC) and factor H (FH) deposits were evaluated with immunofluorescence. Quantitative polymerase chain reaction evaluated the expression of C5aR1, C5L2 genes as well as genes related to tubular injury, inflammation, and profibrotic pathways. Additionally, C5aR1 and C5L2 deposits were evaluated in kidney graft biopsies (KB) from transplant patients with delayed graft function (DGF, n = 12) and compared with Citation: Arias-Cabrales, C.; a control group (n = 8). We observed higher immunofluorescence expression of C5aR1, MAC and FH Rodriguez-Garcia, E.; Gimeno, J.; as higher expression of genes related to tubular injury, inflammatory and profibrotic pathways and Benito, D.; Pérez-Sáez, M.J.; of C5aR1 in the hypoxic cells; whereas, C5L2 gene expression was unaffected by the hypoxic stimulus.
    [Show full text]
  • The Membrane Complement Regulatory Protein CD59 and Its Association with Rheumatoid Arthritis and Systemic Lupus Erythematosus
    Current Medicine Research and Practice 9 (2019) 182e188 Contents lists available at ScienceDirect Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp Review Article The membrane complement regulatory protein CD59 and its association with rheumatoid arthritis and systemic lupus erythematosus * Nibhriti Das a, Devyani Anand a, Bintili Biswas b, Deepa Kumari c, Monika Gandhi c, a Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India b Department of Zoology, Ramjas College, University of Delhi, India c University School of Biotechnology, Guru Gobind Singh Indraprastha University, India article info abstract Article history: The complement cascade consisting of about 50 soluble and cell surface proteins is activated in auto- Received 8 May 2019 immune inflammatory disorders. This contributes to the pathological manifestations in these diseases. In Accepted 30 July 2019 normal health, the soluble and membrane complement regulatory proteins protect the host against Available online 5 August 2019 complement-mediated self-tissue injury by controlling the extent of complement activation within the desired limits for the host's benefit. CD59 is a membrane complement regulatory protein that inhibits the Keywords: formation of the terminal complement complex or membrane attack complex (C5b6789n) which is CD59 generated on complement activation by any of the three pathways, namely, the classical, alternative, and RA SLE the mannose-binding lectin pathway. Animal experiments and human studies have suggested impor- Pathophysiology tance of membrane complement proteins including CD59 in the pathophysiology of rheumatoid arthritis Disease marker (RA) and systemic lupus erythematosus (SLE). Here is a brief review on CD59 and its distribution, structure, functions, and association with RA and SLE starting with a brief introduction on the com- plement system, its activation, the biological functions, and relations of membrane complement regu- latory proteins, especially CD59, with RA and SLE.
    [Show full text]
  • An Anticomplement Agent That Homes to the Damaged Brain and Promotes Recovery After Traumatic Brain Injury in Mice
    An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice Marieta M. Rusevaa,1,2, Valeria Ramagliab,1, B. Paul Morgana, and Claire L. Harrisa,3 aInstitute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and bDepartment of Genome Analysis, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands Edited by Douglas T. Fearon, Cornell University, Cambridge, United Kingdom, and approved September 29, 2015 (received for review July 15, 2015) Activation of complement is a key determinant of neuropathology to rapidly and specifically inhibit MAC at sites of complement and disability after traumatic brain injury (TBI), and inhibition is activation, and test its therapeutic potential in experimental TBI. neuroprotective. However, systemic complement is essential to The construct, termed CD59-2a-CRIg, comprises CD59a linked fight infections, a critical complication of TBI. We describe a to CRIg via the murine IgG2a hinge. CD59a prevents assembly targeted complement inhibitor, comprising complement receptor of MAC in cell membranes (16), whereas CRIg binds C3b/iC3b of the Ig superfamily (CRIg) fused with complement regulator CD59a, deposited at sites of complement activation (17). The IgG2a designed to inhibit membrane attack complex (MAC) assembly at hinge promotes dimerization to increase ligand avidity. CD59- sites of C3b/iC3b deposition. CRIg and CD59a were linked via the 2a-CRIg protected in the TBI model, demonstrating that site- IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b targeted anti-MAC therapeutics may be effective in prevention binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited of secondary neuropathology and improve neurologic recovery MAC formation and prevented complement-mediated lysis in vitro.
    [Show full text]
  • Quantitation of the Number of Molecules of Glycophorins C and D on Normal Red Blood Cells Using Radioiodinatedfab Fragments of Monoclonal Antibodies
    Quantitation of the Number of Molecules of Glycophorins C and D on Normal Red Blood Cells Using RadioiodinatedFab Fragments of Monoclonal Antibodies By Jon Smythe, Brigitte Gardner, andDavid J. Anstee Two rat monoclonal antibodies (BRAC 1 and BRAC 1 1 ) cytes. Fabfragments of BRAC 1 1 and ERIC 10 gave values have been produced. BRAC 1 recognizes an epitope com- of 143,000 molecules GPC per red blood cell (RBC). Fab mon to the human erythrocyte membrane glycoproteins fragments of BRAC1 gave 225,000 molecules of GPC and glycophorin C (GPC) and glycophorin D (GPD). BRAC 11 GPD per RBC. These results indicate that GPC and GPD is specific for GPC. Fabfragments of these antibodies and together are sufficiently abundantto provide membrane at- BRlC 10, a murine monoclonal anti-GPC,were radioiodin- tachment sites for all ofthe protein 4.1 in normal RBCs. ated and used in quantitative binding assays to measure 0 1994 by The American Societyof Hematology. the number of GPC and GPD molecules on normal erythro- HE SHAPE AND deformability of the mature human (200,000)" and those reported for GPC (50,000).7 This nu- Downloaded from http://ashpublications.org/blood/article-pdf/83/6/1668/612763/1668.pdf by guest on 24 September 2021 T erythrocyte is controlled by a flexible two-dimensional merical differencehas led to the suggestion that a significant lattice of proteins, which together comprise the membrane proportion of protein 4.1 in normal erythrocyte membranes skeleton.' The major components of the skeleton are spec- must be bound to sites other than GPC and GPD.3 The trin, actin, ankyrin, and protein 4.1.
    [Show full text]
  • CD Markers Are Routinely Used for the Immunophenotyping of Cells
    ptglab.com 1 CD MARKER ANTIBODIES www.ptglab.com Introduction The cluster of differentiation (abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules. So-called CD markers are routinely used for the immunophenotyping of cells. Despite this use, they are not limited to roles in the immune system and perform a variety of roles in cell differentiation, adhesion, migration, blood clotting, gamete fertilization, amino acid transport and apoptosis, among many others. As such, Proteintech’s mini catalog featuring its antibodies targeting CD markers is applicable to a wide range of research disciplines. PRODUCT FOCUS PECAM1 Platelet endothelial cell adhesion of blood vessels – making up a large portion molecule-1 (PECAM1), also known as cluster of its intracellular junctions. PECAM-1 is also CD Number of differentiation 31 (CD31), is a member of present on the surface of hematopoietic the immunoglobulin gene superfamily of cell cells and immune cells including platelets, CD31 adhesion molecules. It is highly expressed monocytes, neutrophils, natural killer cells, on the surface of the endothelium – the thin megakaryocytes and some types of T-cell. Catalog Number layer of endothelial cells lining the interior 11256-1-AP Type Rabbit Polyclonal Applications ELISA, FC, IF, IHC, IP, WB 16 Publications Immunohistochemical of paraffin-embedded Figure 1: Immunofluorescence staining human hepatocirrhosis using PECAM1, CD31 of PECAM1 (11256-1-AP), Alexa 488 goat antibody (11265-1-AP) at a dilution of 1:50 anti-rabbit (green), and smooth muscle KD/KO Validated (40x objective). alpha-actin (red), courtesy of Nicola Smart. PECAM1: Customer Testimonial Nicola Smart, a cardiovascular researcher “As you can see [the immunostaining] is and a group leader at the University of extremely clean and specific [and] displays Oxford, has said of the PECAM1 antibody strong intercellular junction expression, (11265-1-AP) that it “worked beautifully as expected for a cell adhesion molecule.” on every occasion I’ve tried it.” Proteintech thanks Dr.
    [Show full text]
  • CD59: a Long-Known Complement Inhibitor Has Advanced to a Blood Group System
    B LOOD G ROUP R EVIEW CD59: A long-known complement inhibitor has advanced to a blood group system C. Weinstock, M. Anliker, and I. von Zabern The blood group system number 35 is based on CD59, a 20-kDa by Zalman et al.1 from the group of H.J. Muller-Eberhard in La membrane glycoprotein present on a large number of different Jolla, California, and in 1988 by Schönermark et al. from the cells, including erythrocytes. The major function of CD59 is to group of G.M. Hänsch in Heidelberg (Germany).2 This inhibitor protect cells from complement attack. CD59 binds to complement components C8 and C9 and prevents the polymerization of C9, was published under the designations “HRF (homologous which is required for the formation of the membrane attack restriction factor)” and “C8bp (C8 binding protein),” complex (MAC). Other functions of CD59 in cellular immunity respectively, to describe its properties.1,2 “C8bp” indicates the are less well defined. CD59 is inserted into the membrane by a glycosylphosphatidylinositol (GPI) anchor. A defect of this anchor binding capacity for C8. The name “HRF” points to a species causes lack of this protein from the cell membrane, which leads to incompatibility of this “factor” that provides protection from an enhanced sensitivity towards complement attack. Patients with complement attack more effectively in a homologous (e.g., paroxysmal nocturnal hemoglobinuria (PNH) harbor a varying human erythrocytes as a target of human complement) than in percentage of red blood cell clones with a defect in GPI-anchored proteins, including CD59. The most characteristic symptoms of a heterologous system (e.g., human erythrocytes as a target of this disease are episodes of hemolysis and thromboses.
    [Show full text]
  • Multiomics of Azacitidine-Treated AML Cells Reveals Variable And
    Multiomics of azacitidine-treated AML cells reveals variable and convergent targets that remodel the cell-surface proteome Kevin K. Leunga, Aaron Nguyenb, Tao Shic, Lin Tangc, Xiaochun Nid, Laure Escoubetc, Kyle J. MacBethb, Jorge DiMartinob, and James A. Wellsa,1 aDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; bEpigenetics Thematic Center of Excellence, Celgene Corporation, San Francisco, CA 94158; cDepartment of Informatics and Predictive Sciences, Celgene Corporation, San Diego, CA 92121; and dDepartment of Informatics and Predictive Sciences, Celgene Corporation, Cambridge, MA 02140 Contributed by James A. Wells, November 19, 2018 (sent for review August 23, 2018; reviewed by Rebekah Gundry, Neil L. Kelleher, and Bernd Wollscheid) Myelodysplastic syndromes (MDS) and acute myeloid leukemia of DNA methyltransferases, leading to loss of methylation in (AML) are diseases of abnormal hematopoietic differentiation newly synthesized DNA (10, 11). It was recently shown that AZA with aberrant epigenetic alterations. Azacitidine (AZA) is a DNA treatment of cervical (12, 13) and colorectal (14) cancer cells methyltransferase inhibitor widely used to treat MDS and AML, can induce interferon responses through reactivation of endoge- yet the impact of AZA on the cell-surface proteome has not been nous retroviruses. This phenomenon, termed viral mimicry, is defined. To identify potential therapeutic targets for use in com- thought to induce antitumor effects by activating and engaging bination with AZA in AML patients, we investigated the effects the immune system. of AZA treatment on four AML cell lines representing different Although AZA treatment has demonstrated clinical benefit in stages of differentiation. The effect of AZA treatment on these AML patients, additional therapeutic options are needed (8, 9).
    [Show full text]
  • View Table of Contents
    Table of Contents Preface. xv About the Authors . xvii Section 1: ABO: The Birth of Blood Groups 1. Blood Groups—From Then ’Til Now . .1 Discovery . .1 Response and Reconsideration . .2 Beyond ABO . .4 M, N, and P . .5 Rh . .6 The Antiglobulin Test . .7 The Plot Thickens . .7 References . .8 2. Karl Landsteiner, Father of Blood Groups . .9 Beginnings . .9 Medical School . .11 The Young Researcher . .13 Priority Issues . .16 Decastello and Sturli: Another Blood Group . .18 Other Directions . .19 Life in Vienna . .21 References . .23 3. ABO Grows Up . .27 Transfusion History, 1600 to 1920 . .27 The Blood Groups Gain Attention . .29 Transfusion in World War I . .37 Advances in ABO Blood Group Serology . .39 References . .47 4. Genetics, Eugenics, and Blood Groups . .51 Heredity, 1900 . .52 The Rise of Genetics . .52 Genes and Blood Groups . .53 viii BLOODY BRILLIANT! Genes and Populations . 59 References . 62 5. Karl Landsteiner in New York . 65 At “The Rockefeller” . 65 Landsteiner Returns to the Blood Groups . 68 The Nobel Prize . 71 The Laureate at Work . 73 References . 74 6. Out, Damned Spot! Early Forensic Applications of ABO . 77 What Blood Can Tell . 78 Is It Blood? . 78 Is It Human Blood? . 79 Whose Blood Is It? . 81 References . 85 7. Who’s Your Daddy? ABO and Paternity Testing . 87 Establishing Paternity . 87 Paternity Testing and the Courts: Europe . 89 Paternity Testing and the Courts: Britain . 91 Paternity Testing and the Courts: United States . 92 Lights! Camera! Action! . ..
    [Show full text]
  • Early Complement Activation and Decreased Levels Of
    Early Complement Activation and Decreased Levels of Glycosylphosphatidylinositol-Anchored Complement Inhibitors in Human and Experimental Diabetic Retinopathy Jing Zhang, Chiara Gerhardinger, and Mara Lorenzi Diabetic retinal microangiopathy is characterized by operative in causing retinal vascular damage in diabetes increased permeability, leukostasis, microthrombosis, and how they are triggered are the objects of ongoing and apoptosis of capillary cells, all of which could be investigation. caused or compounded by activation of complement. In Activation of the complement cascade can both com- this study, we observed deposition of C5b-9, the termi- pound and initiate thrombosis, leukostasis, and apoptosis. nal product of complement activation, in the wall of On the one hand, microthrombi and leukostasis can cause ؎ retinal vessels of human eye donors with 9 3 years of ischemia-reperfusion, which activates complement via the type 2 diabetes, but not in the vessels of age-matched nondiabetic donors. C5b-9 often colocalized with von classical pathway (4), and apoptotic endothelial cells can Willebrand factor in luminal endothelium. C1q and C4, trigger the alternative pathway (5). On the other hand, the complement components unique to the classical complement activation is procoagulant, proinflammatory, pathway, were not detected in the diabetic retinas, and proapoptotic (6), and primary activation of comple- suggesting that C5b-9 was generated via the alternative ment on autologous cells can occur because of insufficient pathway, the spontaneous activation of which is regu- activity of plasma and/or cell surface inhibitors. Sponta- lated by complement inhibitors. The diabetic donors neous cleavage of plasma C3 generates C3b, which at- showed a prominent reduction in the retinal levels of taches covalently to the endothelial cell surface through CD55 and CD59, the two complement inhibitors linked to the plasma membrane by glycosylphosphatidylinosi- its reactive thioester group (5).
    [Show full text]
  • Clinical Significance of Antibodies to Antigens in the Raph, John Milton
    R EVIEW Proceedings from the International Society of Blood Transfusion Working Party on Immunohaematology, Workshop on the Clinical Significance of Red Blood Cell Alloantibodies, September 2, 2016, Dubai Clinical significance of antibodies to antigens in the Raph, John Milton Hagen, I, Globoside, Gill, Rh-associated glycoprotein, FORS, JR, LAN, Vel, CD59, and Augustine blood group systems M. Moghaddam and A.A. Naghi This article reviews information on the clinical significance and 6 shared missense mutation c.511C>T (p.Argl71Cys) as of antibodies to antigens in the Raph, John Milton Hagen, I, well as a synonymous single-nucleotide mutation (c.579A>G) Globoside, Gill, Rh-associated glycoprotein, FORS, JR, LAN, Vel, and had no clinical features. Although the CD151 protein is CD59, and Augustine blood group systems. Antibodies to many of the antigens in these groups are rarely encountered because of the critical to cell adhesion and signaling and is implicated in high prevalence of the associated antigens in most populations. cancer progression, its significance in transfusion medicine is For many of these antibodies, the clinical significance—that is, limited to only one report of a hemolytic transfusion reaction the potential to cause reduced survival of transfused antigen- 3 positive red blood cells or a transfusion reaction (e.g., anti-P, (HTR). Least-incompatible RBC units should be selected anti-Jra, and anti-Lan), and/or hemolytic disease of the fetus and for transfusion to patients with anti-MER2.2 No information newborn (e.g., anti-RHAG4 and anti-Vel)—has been documented. on anti-MER2 causing hemolytic disease of the fetus and For other antibodies, their prevalence is so rare that information newborn (HDFN) is available.4 on the clinical significance of their antibodies is not available (e.g., anti-FORS1).
    [Show full text]
  • CD24, CD27, CD36 and CD302 Gene Expression for Outcome Prediction in Patients with Multiple Myeloma
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 58), pp: 98931-98944 Research Paper CD24, CD27, CD36 and CD302 gene expression for outcome prediction in patients with multiple myeloma Elina Alaterre6,2, Sebastien Raimbault6, Hartmut Goldschmidt4,5, Salahedine Bouhya7, Guilhem Requirand1,2, Nicolas Robert1,2, Stéphanie Boireau1,2, Anja Seckinger4,5, Dirk Hose4,5, Bernard Klein1,2,3 and Jérôme Moreaux1,2,3 1Department of Biological Haematology, CHU Montpellier, Montpellier, France 2Institute of Human Genetics, CNRS-UM UMR9002, Montpellier, France 3University of Montpellier, UFR Medecine, Montpellier, France 4Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany 5Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany 6HORIBA Medical, Parc Euromédecine, Montpellier, France 7CHU Montpellier, Department of Clinical Hematology, Montpellier, France Correspondence to: Jérôme Moreaux, email: [email protected] Keywords: multiple myeloma; prognostic factor; gene expression profiling; cluster differentiation Received: February 10, 2017 Accepted: August 27, 2017 Published: October 30, 2017 Copyright: Alaterre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Multiple myeloma (MM) is a B cell neoplasia characterized by clonal plasma cell (PC) proliferation. Minimal residual disease monitoring by multi-parameter flow cytometry is a powerful tool for predicting treatment efficacy and MM outcome. In this study, we compared CD antigens expression between normal and malignant plasma cells to identify new potential markers to discriminate normal from malignant plasma cells, new potential therapeutic targets for monoclonal-based treatments and new prognostic factors.
    [Show full text]