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      Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

      1 , 2 , 1 , 2 , 3 , 4 , 4 , 5 , 1 , 2 , 6 , 7 , 8 , 9 , 8 , 1 , 2 , 10 , 11 , 12 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 13 , 13 , 13 , 1 , 2 , 14 , 14 , 14 , 10 , 15 , 15 , 16 , 17 , 18 , 5 , 19 , 4 , a , 1 , 2 , 20

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          Abstract

          The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

          Abstract

          Chronic myelomonocytic leukaemia is treated with agents that modify DNA methylation but whether they have direct cytotoxic effects is unclear. Here, the authors show that cells from treated patients show marked methylation changes without altered somatic mutation burden, suggesting that cytotoxicity is not a major factor in therapeutic efficacy.

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          Most cited references 36

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          Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.

          The myelodysplastic syndromes (MDSs) are heterogeneous with respect to clinical characteristics, pathologic features, and cytogenetic abnormalities. This heterogeneity is a challenge for evaluating response to treatment. Therapeutic trials in MDS have used various criteria to assess results, making cross-study comparisons problematic. In 2000, an International Working Group (IWG) proposed standardized response criteria for evaluating clinically significant responses in MDS. These criteria included measures of alteration in the natural history of disease, hematologic improvement, cytogenetic response, and improvement in health-related quality of life. The relevance of the response criteria has now been validated prospectively in MDS clinical trials, and they have gained acceptance in research studies and in clinical practice. Because limitations of the IWG criteria have surfaced, based on practical and reported experience, some modifications were warranted. In this report, we present recommendations for revisions of some of the initial criteria.
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            SomaticSniper: identification of somatic point mutations in whole genome sequencing data.

            The sequencing of tumors and their matched normals is frequently used to study the genetic composition of cancer. Despite this fact, there remains a dearth of available software tools designed to compare sequences in pairs of samples and identify sites that are likely to be unique to one sample. In this article, we describe the mathematical basis of our SomaticSniper software for comparing tumor and normal pairs. We estimate its sensitivity and precision, and present several common sources of error resulting in miscalls. Binaries are freely available for download at http://gmt.genome.wustl.edu/somatic-sniper/current/, implemented in C and supported on Linux and Mac OS X. delarson@wustl.edu; lding@wustl.edu Supplementary data are available at Bioinformatics online.
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              Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents

              Blockade of immune checkpoints is emerging as new form of anticancer therapy. We studied the expression of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in CD34+ cells from MDS, CMML and AML patients (N=124). Aberrant up-regulation (≥2 fold) was observed in 34%, 14%, 15% and 8% of the patients respectively. Increased expression of these 4 genes was also observed in PBMNC (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (p=0.018) and CMML (p=0.0128) compared to AML. By immunohistochemical (IHC) analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared to patients that achieved response. Treatment of leukemia cells with decitabine resulted in a dose dependent up-regulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to HMAs. Blockade of this pathway can be a potential therapy in MDS and AML.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                24 February 2016
                2016
                : 7
                Affiliations
                [1 ]INSERM U1170, Gustave Roussy , 114, rue Edouard Vaillant, 94805 Villejuif, France
                [2 ]Department of Hematology, Gustave Roussy Cancer Center , 114, rue Edouard Vaillant, 94805 Villejuif, France
                [3 ]INSERM US23, CNRS UMS3655, Gustave Roussy , 114, rue Edouard Vaillant, 94805 Villejuif, France
                [4 ]Department of Pathology, University of Michigan Medical School , 1500 E Medical Center Dr, Ann Arbor, Michigan 48109, USA
                [5 ]Department of Pathology and Tumour Biology, Kyoto University , Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
                [6 ]Université Lyon 1, UMR CNRS 5558, Université Claude Bernard , 16 rue Raphael Dubois, Lyon 69100, France
                [7 ]Centre Léon Bérard, INSERM U1052, CNRS UMR5286 , 8 Prom. Léa et Napoléon Bullukian, 69008 Lyon, France
                [8 ]Department of Hematology, Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis , 1 Avenue Claude Vellefaux, 75010 Paris, France
                [9 ]Department of Hematology, Assistance Publique–Hôpitaux de Paris , Hôpital Avicenne, 125 Rue de Stalingrad, 93000 Bobigny, France
                [10 ]Cancer Research Institute de Lille, INSERM U837 , 1 Place de Verdun, 59000 Lille, France
                [11 ]Institut de médecine régénératrice, Biothérapie et Institut de biologie computationnelle, INSERM U1040, Université de Montpellier , 80 avenue Augustin Fliche. 34295 Montpellier, France
                [12 ]Department of Hematology, Centre Hospitalier Universitaire de Nîmes, Université Montpellier-Nîmes , 4 Rue du Professeur Robert Debré, 30029 Nîmes, France
                [13 ]Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research , 384 Victoria Street, Darlinghurst New South Wales 2010, Australia
                [14 ]Centre National de Génotypage , 2 rue Gaston Crémieux CP 5721, 91 057 Evry, France
                [15 ]Cancer Genome Project, Wellcome Trust Sanger Institute , Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                [16 ]Theoretical Biology and Biophysics, Los Alamos National Laboratory , P.O. Box 1663, Los Alamos, New Mexico 87545, USA
                [17 ]Center for Nonlinear Studies, Los Alamos National Laboratory , P.O. Box 1663, Los Alamos, New Mexico 87545, USA
                [18 ]Department of Hematology, Malignant hematology, H. Lee Moffitt Cancer Center , 12902 USF Magnolia Drive, Tampa, Florida 33612, USA
                [19 ]Department of Biostatistics, Gustave Roussy Cancer Center , 114 rue Edouard Vaillant, 94805 Villejuif, France
                [20 ]Department of Hematology, Faculty of Medicine, University Paris-Sud , 63 Rue Gabriel Péri, 94270 Le Kremlin-Bicêtre, France
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                ncomms10767
                10.1038/ncomms10767
                4770084
                26908133
                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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