Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Identifieur interne : 000758 ( Pmc/Curation ); précédent : 000757; suivant : 000759Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Auteurs : Jane Merlevede [France] ; Nathalie Droin [France] ; Tingting Qin [États-Unis] ; Kristen Meldi [États-Unis] ; Kenichi Yoshida [Japon] ; Margot Morabito [France] ; Emilie Chautard [France] ; Didier Auboeuf [France] ; Pierre Fenaux [France] ; Thorsten Braun [France] ; Raphael Itzykson [France] ; Stéphane De Botton [France] ; Bruno Quesnel [France] ; Thérèse Commes [France] ; Eric Jourdan [France] ; William Vainchenker [France] ; Olivier Bernard [France] ; Noemie Pata-Merci [France] ; Stéphanie Solier [France] ; Velimir Gayevskiy [Australie] ; Marcel E. Dinger [Australie] ; Mark J. Cowley [Australie] ; Dorothée Selimoglu-Buet [France] ; Vincent Meyer [France] ; François Artiguenave [France] ; Jean-François Deleuze [France] ; Claude Preudhomme [France] ; Michael R. Stratton [Royaume-Uni] ; Ludmil B. Alexandrov [Royaume-Uni, États-Unis] ; Eric Padron [États-Unis] ; Seishi Ogawa [Japon] ; Serge Koscielny [France] ; Maria Figueroa [États-Unis] ; Eric Solary [France]Source :
- Nature Communications [ 2041-1723 ] ; 2016.
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.
Url:
DOI: 10.1038/ncomms10767
PubMed: 26908133
PubMed Central: 4770084
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strict</wicri:regionArea></affiliation></author><author><name sortKey="Vainchenker, William" sort="Vainchenker, William" uniqKey="Vainchenker W" first="William" last="Vainchenker">William Vainchenker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bernard, Olivier" sort="Bernard, Olivier" uniqKey="Bernard O" first="Olivier" last="Bernard">Olivier Bernard</name><affiliation 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xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Solier, Stephanie" sort="Solier, Stephanie" uniqKey="Solier S" first="Stéphanie" last="Solier">Stéphanie Solier</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gayevskiy, Velimir" sort="Gayevskiy, Velimir" uniqKey="Gayevskiy V" first="Velimir" 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Dinger</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research</institution>, 384 Victoria Street, Darlinghurst New South Wales 2010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cowley, Mark J" sort="Cowley, Mark J" uniqKey="Cowley M" first="Mark J." last="Cowley">Mark J. Cowley</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research</institution>, 384 Victoria Street, Darlinghurst New South Wales 2010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Selimoglu Buet, Dorothee" sort="Selimoglu Buet, Dorothee" uniqKey="Selimoglu Buet D" first="Dorothée" last="Selimoglu-Buet">Dorothée Selimoglu-Buet</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Meyer, Vincent" sort="Meyer, Vincent" uniqKey="Meyer V" first="Vincent" last="Meyer">Vincent Meyer</name><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Artiguenave, Francois" sort="Artiguenave, Francois" uniqKey="Artiguenave F" first="François" last="Artiguenave">François Artiguenave</name><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Deleuze, Jean Francois" sort="Deleuze, Jean Francois" uniqKey="Deleuze J" first="Jean-François" last="Deleuze">Jean-François Deleuze</name><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Preudhomme, Claude" sort="Preudhomme, Claude" uniqKey="Preudhomme C" first="Claude" last="Preudhomme">Claude Preudhomme</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Cancer Research Institute de Lille, INSERM U837</institution>, 1 Place de Verdun, 59000 Lille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation wicri:level="1"><nlm:aff id="a15"><institution>Cancer Genome Project, Wellcome Trust Sanger Institute</institution>, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B." last="Alexandrov">Ludmil B. Alexandrov</name><affiliation wicri:level="1"><nlm:aff id="a15"><institution>Cancer Genome Project, Wellcome Trust Sanger Institute</institution>, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a16"><institution>Theoretical Biology and Biophysics, Los Alamos National Laboratory</institution>, P.O. Box 1663, Los Alamos, New Mexico 87545,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a17"><institution>Center for Nonlinear Studies, Los Alamos National Laboratory</institution>, P.O. Box 1663, Los Alamos, New Mexico 87545,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Padron, Eric" sort="Padron, Eric" uniqKey="Padron E" first="Eric" last="Padron">Eric Padron</name><affiliation wicri:level="1"><nlm:aff id="a18"><institution>Department of Hematology, Malignant hematology, H. Lee Moffitt Cancer Center</institution>, 12902 USF Magnolia Drive, Tampa, Florida 33612,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ogawa, Seishi" sort="Ogawa, Seishi" uniqKey="Ogawa S" first="Seishi" last="Ogawa">Seishi Ogawa</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Pathology and Tumour Biology, Kyoto University</institution>, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Koscielny, Serge" sort="Koscielny, Serge" uniqKey="Koscielny S" first="Serge" last="Koscielny">Serge Koscielny</name><affiliation wicri:level="1"><nlm:aff id="a19"><institution>Department of Biostatistics, Gustave Roussy Cancer Center</institution>, 114 rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Figueroa, Maria" sort="Figueroa, Maria" uniqKey="Figueroa M" first="Maria" last="Figueroa">Maria Figueroa</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Pathology, University of Michigan Medical School</institution>, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Solary, Eric" sort="Solary, Eric" uniqKey="Solary E" first="Eric" last="Solary">Eric Solary</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a20"><institution>Department of Hematology, Faculty of Medicine, University Paris-Sud</institution>, 63 Rue Gabriel Péri, 94270 Le Kremlin-Bicêtre,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26908133</idno><idno type="pmc">4770084</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770084</idno><idno type="RBID">PMC:4770084</idno><idno type="doi">10.1038/ncomms10767</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000759</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000759</idno><idno type="wicri:Area/Pmc/Curation">000758</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000758</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents</title><author><name sortKey="Merlevede, Jane" sort="Merlevede, Jane" uniqKey="Merlevede J" first="Jane" last="Merlevede">Jane Merlevede</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Droin, Nathalie" sort="Droin, Nathalie" uniqKey="Droin N" first="Nathalie" last="Droin">Nathalie Droin</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>INSERM US23, CNRS UMS3655, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Qin, Tingting" sort="Qin, Tingting" uniqKey="Qin T" first="Tingting" last="Qin">Tingting Qin</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Pathology, University of Michigan Medical School</institution>, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Meldi, Kristen" sort="Meldi, Kristen" uniqKey="Meldi K" first="Kristen" last="Meldi">Kristen Meldi</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Pathology, University of Michigan Medical School</institution>, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yoshida, Kenichi" sort="Yoshida, Kenichi" uniqKey="Yoshida K" first="Kenichi" last="Yoshida">Kenichi Yoshida</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Pathology and Tumour Biology, Kyoto University</institution>, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Morabito, Margot" sort="Morabito, Margot" uniqKey="Morabito M" first="Margot" last="Morabito">Margot Morabito</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chautard, Emilie" sort="Chautard, Emilie" uniqKey="Chautard E" first="Emilie" last="Chautard">Emilie Chautard</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Université Lyon 1, UMR CNRS 5558, Université Claude Bernard</institution>, 16 rue Raphael Dubois, Lyon 69100,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Auboeuf, Didier" sort="Auboeuf, Didier" uniqKey="Auboeuf D" first="Didier" last="Auboeuf">Didier Auboeuf</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Centre Léon Bérard, INSERM U1052, CNRS UMR5286</institution>, 8 Prom. Léa et Napoléon Bullukian, 69008 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fenaux, Pierre" sort="Fenaux, Pierre" uniqKey="Fenaux P" first="Pierre" last="Fenaux">Pierre Fenaux</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology, Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis</institution>, 1 Avenue Claude Vellefaux, 75010 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Braun, Thorsten" sort="Braun, Thorsten" uniqKey="Braun T" first="Thorsten" last="Braun">Thorsten Braun</name><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Hematology, Assistance Publique–Hôpitaux de Paris</institution>, Hôpital Avicenne, 125 Rue de Stalingrad, 93000 Bobigny,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Itzykson, Raphael" sort="Itzykson, Raphael" uniqKey="Itzykson R" first="Raphael" last="Itzykson">Raphael Itzykson</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology, Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis</institution>, 1 Avenue Claude Vellefaux, 75010 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="De Botton, Stephane" sort="De Botton, Stephane" uniqKey="De Botton S" first="Stéphane" last="De Botton">Stéphane De Botton</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Quesnel, Bruno" sort="Quesnel, Bruno" uniqKey="Quesnel B" first="Bruno" last="Quesnel">Bruno Quesnel</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Cancer Research Institute de Lille, INSERM U837</institution>, 1 Place de Verdun, 59000 Lille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Commes, Therese" sort="Commes, Therese" uniqKey="Commes T" first="Thérèse" last="Commes">Thérèse Commes</name><affiliation wicri:level="1"><nlm:aff id="a11"><institution>Institut de médecine régénératrice, Biothérapie et Institut de biologie computationnelle, INSERM U1040, Université de Montpellier</institution>, 80 avenue Augustin Fliche. 34295 Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jourdan, Eric" sort="Jourdan, Eric" uniqKey="Jourdan E" first="Eric" last="Jourdan">Eric Jourdan</name><affiliation wicri:level="1"><nlm:aff id="a12"><institution>Department of Hematology, Centre Hospitalier Universitaire de Nîmes, Université Montpellier-Nîmes</institution>, 4 Rue du Professeur Robert Debré, 30029 Nîmes,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vainchenker, William" sort="Vainchenker, William" uniqKey="Vainchenker W" first="William" last="Vainchenker">William Vainchenker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bernard, Olivier" sort="Bernard, Olivier" uniqKey="Bernard O" first="Olivier" last="Bernard">Olivier Bernard</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pata Merci, Noemie" sort="Pata Merci, Noemie" uniqKey="Pata Merci N" first="Noemie" last="Pata-Merci">Noemie Pata-Merci</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>INSERM US23, CNRS UMS3655, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Solier, Stephanie" sort="Solier, Stephanie" uniqKey="Solier S" first="Stéphanie" last="Solier">Stéphanie Solier</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gayevskiy, Velimir" sort="Gayevskiy, Velimir" uniqKey="Gayevskiy V" first="Velimir" last="Gayevskiy">Velimir Gayevskiy</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research</institution>, 384 Victoria Street, Darlinghurst New South Wales 2010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dinger, Marcel E" sort="Dinger, Marcel E" uniqKey="Dinger M" first="Marcel E." last="Dinger">Marcel E. Dinger</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research</institution>, 384 Victoria Street, Darlinghurst New South Wales 2010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cowley, Mark J" sort="Cowley, Mark J" uniqKey="Cowley M" first="Mark J." last="Cowley">Mark J. Cowley</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research</institution>, 384 Victoria Street, Darlinghurst New South Wales 2010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Selimoglu Buet, Dorothee" sort="Selimoglu Buet, Dorothee" uniqKey="Selimoglu Buet D" first="Dorothée" last="Selimoglu-Buet">Dorothée Selimoglu-Buet</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Meyer, Vincent" sort="Meyer, Vincent" uniqKey="Meyer V" first="Vincent" last="Meyer">Vincent Meyer</name><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Artiguenave, Francois" sort="Artiguenave, Francois" uniqKey="Artiguenave F" first="François" last="Artiguenave">François Artiguenave</name><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Deleuze, Jean Francois" sort="Deleuze, Jean Francois" uniqKey="Deleuze J" first="Jean-François" last="Deleuze">Jean-François Deleuze</name><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Preudhomme, Claude" sort="Preudhomme, Claude" uniqKey="Preudhomme C" first="Claude" last="Preudhomme">Claude Preudhomme</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Cancer Research Institute de Lille, INSERM U837</institution>, 1 Place de Verdun, 59000 Lille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation wicri:level="1"><nlm:aff id="a15"><institution>Cancer Genome Project, Wellcome Trust Sanger Institute</institution>, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B." last="Alexandrov">Ludmil B. Alexandrov</name><affiliation wicri:level="1"><nlm:aff id="a15"><institution>Cancer Genome Project, Wellcome Trust Sanger Institute</institution>, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a16"><institution>Theoretical Biology and Biophysics, Los Alamos National Laboratory</institution>, P.O. Box 1663, Los Alamos, New Mexico 87545,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a17"><institution>Center for Nonlinear Studies, Los Alamos National Laboratory</institution>, P.O. Box 1663, Los Alamos, New Mexico 87545,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Padron, Eric" sort="Padron, Eric" uniqKey="Padron E" first="Eric" last="Padron">Eric Padron</name><affiliation wicri:level="1"><nlm:aff id="a18"><institution>Department of Hematology, Malignant hematology, H. Lee Moffitt Cancer Center</institution>, 12902 USF Magnolia Drive, Tampa, Florida 33612,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ogawa, Seishi" sort="Ogawa, Seishi" uniqKey="Ogawa S" first="Seishi" last="Ogawa">Seishi Ogawa</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Pathology and Tumour Biology, Kyoto University</institution>, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Koscielny, Serge" sort="Koscielny, Serge" uniqKey="Koscielny S" first="Serge" last="Koscielny">Serge Koscielny</name><affiliation wicri:level="1"><nlm:aff id="a19"><institution>Department of Biostatistics, Gustave Roussy Cancer Center</institution>, 114 rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Figueroa, Maria" sort="Figueroa, Maria" uniqKey="Figueroa M" first="Maria" last="Figueroa">Maria Figueroa</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Pathology, University of Michigan Medical School</institution>, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Solary, Eric" sort="Solary, Eric" uniqKey="Solary E" first="Eric" last="Solary">Eric Solary</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a20"><institution>Department of Hematology, Faculty of Medicine, University Paris-Sud</institution>, 63 Rue Gabriel Péri, 94270 Le Kremlin-Bicêtre,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Vardiman, J W" uniqKey="Vardiman J">J. W. Vardiman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Padron, E" uniqKey="Padron E">E. Padron</name></author><author><name sortKey="Steensma, D P" uniqKey="Steensma D">D. P. Steensma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jankowska, A M" uniqKey="Jankowska A">A. M. Jankowska</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Itzykson, R" uniqKey="Itzykson R">R. Itzykson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kon, A" uniqKey="Kon A">A. 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rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a20">20</xref></contrib><aff id="a1"><label>1</label><institution>INSERM U1170, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></aff><aff id="a2"><label>2</label><institution>Department of Hematology, Gustave Roussy Cancer Center</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></aff><aff id="a3"><label>3</label><institution>INSERM US23, CNRS UMS3655, Gustave Roussy</institution>, 114, rue Edouard Vaillant, 94805 Villejuif,<country>France</country></aff><aff id="a4"><label>4</label><institution>Department of Pathology, University of Michigan Medical School</institution>, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109,<country>USA</country></aff><aff id="a5"><label>5</label><institution>Department of Pathology and Tumour Biology, Kyoto University</institution>, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501,<country>Japan</country></aff><aff id="a6"><label>6</label><institution>Université Lyon 1, UMR CNRS 5558, Université Claude Bernard</institution>, 16 rue Raphael Dubois, Lyon 69100,<country>France</country></aff><aff id="a7"><label>7</label><institution>Centre Léon Bérard, INSERM U1052, CNRS UMR5286</institution>, 8 Prom. Léa et Napoléon Bullukian, 69008 Lyon,<country>France</country></aff><aff id="a8"><label>8</label><institution>Department of Hematology, Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis</institution>, 1 Avenue Claude Vellefaux, 75010 Paris,<country>France</country></aff><aff id="a9"><label>9</label><institution>Department of Hematology, Assistance Publique–Hôpitaux de Paris</institution>, Hôpital Avicenne, 125 Rue de Stalingrad, 93000 Bobigny,<country>France</country></aff><aff id="a10"><label>10</label><institution>Cancer Research Institute de Lille, INSERM U837</institution>, 1 Place de Verdun, 59000 Lille,<country>France</country></aff><aff id="a11"><label>11</label><institution>Institut de médecine régénératrice, Biothérapie et Institut de biologie computationnelle, INSERM U1040, Université de Montpellier</institution>, 80 avenue Augustin Fliche. 34295 Montpellier,<country>France</country></aff><aff id="a12"><label>12</label><institution>Department of Hematology, Centre Hospitalier Universitaire de Nîmes, Université Montpellier-Nîmes</institution>, 4 Rue du Professeur Robert Debré, 30029 Nîmes,<country>France</country></aff><aff id="a13"><label>13</label><institution>Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research</institution>, 384 Victoria Street, Darlinghurst New South Wales 2010,<country>Australia</country></aff><aff id="a14"><label>14</label><institution>Centre National de Génotypage</institution>, 2 rue Gaston Crémieux CP 5721, 91 057 Evry,<country>France</country></aff><aff id="a15"><label>15</label><institution>Cancer Genome Project, Wellcome Trust Sanger Institute</institution>, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA,<country>UK</country></aff><aff id="a16"><label>16</label><institution>Theoretical Biology and Biophysics, Los Alamos National Laboratory</institution>, P.O. Box 1663, Los Alamos, New Mexico 87545,<country>USA</country></aff><aff id="a17"><label>17</label><institution>Center for Nonlinear Studies, Los Alamos National Laboratory</institution>, P.O. Box 1663, Los Alamos, New Mexico 87545,<country>USA</country></aff><aff id="a18"><label>18</label><institution>Department of Hematology, Malignant hematology, H. Lee Moffitt Cancer Center</institution>, 12902 USF Magnolia Drive, Tampa, Florida 33612,<country>USA</country></aff><aff id="a19"><label>19</label><institution>Department of Biostatistics, Gustave Roussy Cancer Center</institution>, 114 rue Edouard Vaillant, 94805 Villejuif,<country>France</country></aff><aff id="a20"><label>20</label><institution>Department of Hematology, Faculty of Medicine, University Paris-Sud</institution>, 63 Rue Gabriel Péri, 94270 Le Kremlin-Bicêtre,<country>France</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>eric.solary@gustaveroussy.fr</email></corresp><fn id="n1"><label>*</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>24</day><month>02</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>7</volume><elocation-id>10767</elocation-id><history><date date-type="received"><day>12</day><month>06</month><year>2015</year></date><date date-type="accepted"><day>19</day><month>01</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>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 <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>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.</p></abstract><abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms10767-i1.jpg"></inline-graphic>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.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Somatic variants in coding regions identified by whole-exome sequencing.</title><p>WES was performed in 49 chronic myelomonocytic leukaemia samples. (<bold>a</bold>) Number and type of somatic mutations identified in each patient designated as UPN, showing a majority of nonsynonymous variants. (<bold>b</bold>) Repartition of the 680 validated somatic variants identified in the 49 patients. (<bold>c</bold>) Repartition of base changes with transitions in black and transversions in grey. (<bold>d</bold>) Of the 36 recurrently mutated genes identified by WES, 26 are actively transcribed in CD14<sup>+</sup> cells and CD34<sup>+</sup> cells (according to Gene Expression Omnibus at <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/geo/">http://www.ncbi.nlm.nih.gov/geo/</ext-link>). These 26 recurrently mutated genes are classified according to their function, including epigenetic regulation, pre-messenger RNA splicing, and signal transduction. Colours indicate the type of mutation. Two colours separated by a slash indicate two distinct mutations in the same gene.</p></caption><graphic xlink:href="ncomms10767-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Somatic variants in coding and non-coding regions identified by whole-genome sequencing.</title><p>WGS was performed in 17 chronic myelomonocytic leukaemia samples (including one analysed by WES). (<bold>a</bold>) Number of somatic single-nucleotide variants and short insertions/deletions in each patient. (<bold>b</bold>) Repartition of the 8077 somatic variants, expressed as numbers of variants per gigabase, identified across the genomic regions. Mean and 95% confidence intervals (<italic>n</italic>=17) are shown. (<bold>c</bold>) Repartition of base changes with transitions in black and transversions in grey. (<bold>d</bold>) Repartition of the 207 somatic variants identified in coding regions. (<bold>e</bold>) Mutational signatures extracted from whole genomic analyses. (<bold>f</bold>) Potential hotspots of mutations (two variants less than 250 bp apart) including nine in coding regions of driver genes (including <italic>TET2</italic>, <italic>ASXL1</italic>, <italic>SRSF2</italic>, <italic>CBL</italic> and <italic>NRAS</italic>), two in intronic regions of <italic>PDS5A</italic> and <italic>NHLRC2</italic>, one in 3'UTR of <italic>ZFP36L2</italic>, six in intergenic regions and 1 in the mitochondrial chromosome. Numbers between comas indicate the chromosome number.</p></caption><graphic xlink:href="ncomms10767-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>TET3–R1548H mutation inhibits 5hmC modification.</title><p>(<bold>a</bold>) Single cell analysis of TET3R1548H, TET2S1708fsX11 and TET2L1819X mutations in sorted CD14<sup>+</sup> cells from UPN22. (<bold>b</bold>) <italic>TET2</italic> and <italic>TET3</italic> gene expression measured by quantitative reverse transcriptase–PCR in HEK293T cells transfected with the pcDNA3.1 empty vector or pcDNA3.1 encoding wild-type (TET3-WT) and R1548H TET3 (TET3-MUT). Reporter gene: <italic>RPL32</italic>. Results are related to pcDNA3.1 control. Error bars represent mean±standard deviation of triplicates. (<bold>c</bold>) Dot blot analysis of 5-hydroxymethylcytosine (5hmC) on genomic DNA (4-fold serial dilutions in ng) isolated from HEK293T cells transfected as in <bold>b</bold>.</p></caption><graphic xlink:href="ncomms10767-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Serial whole-exome sequencing analysis of somatic variants.</title><p>WES of sorted peripheral blood monocyte DNA was performed two- to fivefold in 17 patients at a mean interval of 14±8 months (range: 4–32). The clonal evolution of recurrently mutated genes is shown. UPN indicates the patient number. A selection of the variants detected by the first whole-exome sequencing is shown (all the variants identified in each individual patient are depicted in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 5</xref>). All the changes in variant allele frequency and new variants detected by repeating whole-exome sequencing are shown. Black indicates the founding clone and subsequent subclones are shown in violet, red, orange, and green, successively. Patients were either untreated (<bold>a</bold>) or treated with either azacytidine (AZA) or decitabine (DAC) as indicated in red. Blue dash lines indicate WES. (<bold>b</bold>) Patients with a stable disease on therapy. (<bold>c</bold>) Responding patients.</p></caption><graphic xlink:href="ncomms10767-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Serial whole-genome sequencing in a 5-AZA exceptional responder.</title><p>WGS was performed before 5-azatidine treatment (baseline), in complete response (remission) and at disease progression (relapse). (<bold>a</bold>,<bold>b</bold>) Scatter plot of somatic variants identified at baseline, remission, and progression. Chromosomal location is color coded and the size of the object denotes its predicted impact on protein function. High impact variants are those that are predicted to have the highest likelihood of altering protein expression or function such as frameshifts or nonsense variants. Circles denote single-nucleotide variants and triangles denote insertions or deletions. (<bold>c</bold>,<bold>d</bold>) Scatter plot of all variants identified with Freebayes at baseline, remission, and progression. Chromosomal location is color coded. (<bold>e</bold>) Copy number changes as identified from whole-genome sequencing data using Sequenza.</p></caption><graphic xlink:href="ncomms10767-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Evolution of gene expression pattern on hypomethylating agent therapy.</title><p>Gene expression was analysed at two time points in sorted peripheral blood monocytes from 9 chronic myelomonocytic leukaemia patients, including three untreated and six treated with either azacytidine or decitabine. These cases were randomly selected in each group. Three treated patients remained stable on therapy (non-responders) whereas the three others were responders. In treated patients, the first sample was collected before treatment, the second one after at least 5 drug cycles and just before the next cycle. Volcano plots of genes differentially expressed between these two time points are shown in non-responders (<bold>a</bold>) and in responders (<bold>b</bold>). The name of the most differentially deregulated genes is indicated. No significant change in gene expression was detected in untreated patients analysed twice at an at least 5-month interval (see also <xref ref-type="table" rid="t1">Table 1</xref>). Each dot (<italic>N</italic>=24,563) represents a gene; green dots, padj ≤0.05, orange dots, abs (log<sub>2</sub> (fold change)) ≥1 and red dots, padj ≤0.05 and abs(log<sub>2</sub> (fold change)) ≥1. (<bold>c</bold>) Quantitative reverse transcriptase–PCR validation of the differential expression of 8 genes in 6 responders (3 studied by RNA sequencing in <bold>b</bold> and 3 additional cases) and 10 non-responders (3 studied by RNA sequencing in <bold>a</bold> and 7 additional cases). Normalizer gene, <italic>RPL32</italic>. Similar results were obtained with two other normalizer genes, <italic>GUS</italic> and <italic>HPRT</italic> (<xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 8</xref>). (<bold>d</bold>) Significant changes in pathways detected by analysing RNA sequencing data with Ingenuity (<ext-link ext-link-type="uri" xlink:href="http://www.ingenuity.com/products/ipa">www.ingenuity.com/products/ipa</ext-link>).</p></caption><graphic xlink:href="ncomms10767-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>Evolution of DNA methylation pattern on hypomethylating drug therapy.</title><p>Methylation was analysed at two time points in sorted monocytes from nine chronic myelomonocytic leukaemia patients, including three untreated and six treated with either azacytidine or decitabine. Three treated patients remained stable on therapy (non-responders) whereas the three others were responders. In treated patients, the first sample was collected before treatment, the second one after at least five drug cycles and just before the next cycle. (<bold>a</bold>,<bold>b</bold>) Chromosome ideograms representing differentially methylated regions (DMRs) in non-responders (<bold>a</bold>) and in responders (<bold>b</bold>) are shown. Reduction in DNA methylation is in green, whereas increased methylation is in pink. (<bold>c</bold>,<bold>d</bold>) Barplots showing the percentage of genomic regions with significant changes in DNA methylation in non-responders (<bold>c</bold>) and in responders (<bold>d</bold>) are also shown. No change was identified in the 3 untreated patients (<xref ref-type="table" rid="t1">Table 1</xref>). (<bold>e</bold>) Violin plots showing the evolution of global methylation change in each patient (untreated patients in grey, treated with a stable disease (non-responders) in blue, treated responders in red with the lighter color indicating the earliest analysis.</p></caption><graphic xlink:href="ncomms10767-f7"></graphic></fig><fig id="f8"><label>Figure 8</label><caption><title>Relationship between changes in DNA methylation and in gene expression.</title><p>Venn diagrams of interactions between differentially methylated regions (DMR, red circles) and differentially expressed genes (upregulated in blue; downregulated in green) as defined in <xref ref-type="fig" rid="f5">Fig. 5</xref> (padj ≤0.05 and abs(log<sub>2</sub> (fold change)) ≥1).</p></caption><graphic xlink:href="ncomms10767-f8"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Changes induced by hypomethylating agents in gene expression and DNA methylation.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="."></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" char="." charoff="50">Untreated</th><th align="center" valign="top" char="." charoff="50">Treated non-responders</th><th align="center" valign="top" char="." charoff="50">Treated responders</th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Number of patients</td><td align="char" valign="top" char="." charoff="50">3</td><td align="char" valign="top" char="." charoff="50">3</td><td align="char" valign="top" char="." charoff="50">3</td></tr><tr><td align="left" valign="top" charoff="50">Time between analyses (months) mean±s.d.</td><td align="center" valign="top" char="." charoff="50">17±10</td><td align="center" valign="top" char="." charoff="50">9±3</td><td align="center" valign="top" char="." charoff="50">27±17</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td> </td><td> </td><td> </td></tr><tr><td colspan="4" align="center" valign="top" charoff="50"><italic>Changes in gene expression</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Up</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">12</td><td align="char" valign="top" char="." charoff="50">343</td></tr><tr><td align="left" valign="top" charoff="50"> Down</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">51</td><td align="char" valign="top" char="." charoff="50">170</td></tr><tr><td align="left" valign="top" charoff="50"> Total</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">63</td><td align="char" valign="top" char="." charoff="50">513</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td> </td><td> </td><td> </td></tr><tr><td colspan="4" align="center" valign="top" charoff="50"><italic>Differentially methylated regions</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Up</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">28</td><td align="char" valign="top" char="." charoff="50">19</td></tr><tr><td align="left" valign="top" charoff="50"> Down</td><td align="char" valign="top" char="." charoff="50">1</td><td align="char" valign="top" char="." charoff="50">75</td><td align="char" valign="top" char="." charoff="50">35,895</td></tr><tr><td align="left" valign="top" charoff="50"> Total</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">103</td><td align="char" valign="top" char="." charoff="50">35,914</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>Genomic analyses were performed at two time points in sorted peripheral blood monocytes of nine chronic myelomonocytic leukaemia patients, including three left untreated and six patients treated with either azacytidine or decitabine. Among treated patients, 3 had a stable disease under therapy (non-responders) and three demonstrated clinical response (<xref ref-type="fig" rid="f4">Figs 4</xref> and <xref ref-type="fig" rid="f5">5</xref>). The first sample was collected before treatment, the second after at least five cycles of either azacytidine or decitabine, just before the next cycle. We measured the number of differentially expressed genes having abs(log<sub>2</sub> (fold change)) ≥1 between T1 and T2, and the number of differentially methylated regions having ≥25% difference between T1 and T2.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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