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      A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis

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          Abstract

          Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of “ET” patients.

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          Most cited references61

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          Granules of the human neutrophilic polymorphonuclear leukocyte.

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            Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule.

            Carcinoembryonic antigen (CEA) is a member of a family of cell surface glycoproteins that are produced in excess in essentially all human colon carcinomas and in a high proportion of carcinomas at many other sites. The function of this widely used tumor marker and its relevance to malignant transformation is therefore of considerable interest. We demonstrate here that CEA mediates Ca2+-independent, homotypic aggregation of cultured human colon adenocarcinoma cells (LS-180) and rodent cells transfected with functional CEA cDNA. Furthermore, CEA can effect the homotypic sorting of cells in heterogeneous populations of aggregating cells. CEA can thus be considered a new addition to the family of intercellular adhesion molecules. We also show that, whereas CEA is localized mainly to epithelial cell membranes facing the lumen in normal adult intestine, it is found on adjacent cell membranes in both embryonic intestine and colonic tumors. A model for the role of CEA in the tissue architecture of adult, embryonic, and aberrant tumor intestinal epithelium is presented.
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              CEACAMs: their role in physiology and pathophysiology

              Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) belong to a group of mammalian immunoglobulin-related glycoproteins. They are involved in cell–cell recognition and modulate cellular processes that range from the shaping of tissue architecture and neovascularization to the regulation of insulin homeostasis and T-cell proliferation. CEACAMs have also been identified as receptors for host-specific viruses and bacteria in mice and humans, respectively, making these proteins an interesting example of pathogen–host co-evolution. Forward and reverse genetics in the mouse now provide powerful novel models to elucidate the action of CEACAM family members in vivo.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                31 August 2016
                2016
                : 11
                : 8
                : e0161570
                Affiliations
                [1 ]Department of Hematology, Zealand University Hospital, Roskilde, Denmark
                [2 ]Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
                [3 ]Department of Hematology X, Odense University Hospital, Odense, Denmark
                [4 ]Department of Pathology, Naestved Hospital, Naestved, Denmark
                [5 ]Department of Pathology, Lund University Hospital, Lund, Sweden
                [6 ]Department of Pathology, University of Aarhus, Aarhus, Denmark
                [7 ]Institute of Pathology, University of Cologne, Köln, Germany
                [8 ]Department of Hematology L, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
                University of Massachusetts Medical School, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: HCH VS MT TAK JT ABM KN.

                • Performed the experiments: HCH VS ABM JT ME IS HB MB LK.

                • Analyzed the data: HCH VS MT TAK MB.

                • Contributed reagents/materials/analysis tools: NB RDS TSL CR MKJ OWB HCH.

                • Wrote the paper: HCH ABM VS.

                • Crtical revision of the manuscript and final approval of the version to be published: HCH VS MB TSL MT CR ABM HB IS LK ME RDS TAK OWB NB MKJ JT KN.

                Article
                PONE-D-16-05556
                10.1371/journal.pone.0161570
                5007012
                27579896
                953408b6-e77c-41fd-a0f4-06b4b3b3bb61
                © 2016 Skov et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 February 2016
                : 8 August 2016
                Page count
                Figures: 3, Tables: 3, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100008392, Sundhed og Sygdom, Det Frie Forskningsråd;
                Award ID: 271-05-0118
                Award Recipient :
                The study has received grants from The Danish Council for independent Research Medical Sciences ( http://ufm.dk/forskning-og-innovation/rad-og-udvalg/det-frie-forskningsrad/radet/dff-sundhed-og-sygdom).
                Categories
                Research Article
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
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                Pathology and Laboratory Medicine
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                Hematology
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                Medicine and Health Sciences
                Immunology
                Immune Cells
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                Biology and Life Sciences
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                Bone Marrow
                Medicine and Health Sciences
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                Immune Physiology
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                Biology and Life Sciences
                Immunology
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                Medicine and Health Sciences
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                Custom metadata
                Data are available from Gene Expression Omnibus ( http://www.ncbi.nlm.nih.gov/geo; accession no. GSE26049).

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