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

Jane Merlevede, Nathalie Droin, Tingting Qin, Kristen Meldi, Kenichi Yoshida, Margot Morabito, Emilie Chautard, Didier Auboeuf, Pierre Fenaux, Thorsten Braun, Raphael Itzykson, Stéphane de Botton, Bruno Quesnel, Thérèse Commes, Eric Jourdan, William Vainchenker, Olivier Bernard, Noemie Pata-Merci, Stéphanie Solier, Velimir Gayevskiy, Marcel E. Dinger, Mark J. Cowley, Dorothée Selimoglu-Buet, Vincent Meyer, François Artiguenave, Jean-François Deleuze, Claude Preudhomme, Michael R. Stratton, Ludmil B. Alexandrov, Eric Padron, Seishi Ogawa, Serge Koscielny, Maria Figueroa and Eric Solary ()
Additional contact information
Jane Merlevede: INSERM U1170, Gustave Roussy
Nathalie Droin: INSERM U1170, Gustave Roussy
Tingting Qin: University of Michigan Medical School
Kristen Meldi: University of Michigan Medical School
Kenichi Yoshida: Kyoto University
Margot Morabito: INSERM U1170, Gustave Roussy
Emilie Chautard: Université Lyon 1, UMR CNRS 5558, Université Claude Bernard
Didier Auboeuf: Centre Léon Bérard, INSERM U1052, CNRS UMR5286
Pierre Fenaux: Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis
Thorsten Braun: Assistance Publique–Hôpitaux de Paris
Raphael Itzykson: Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis
Stéphane de Botton: INSERM U1170, Gustave Roussy
Bruno Quesnel: Cancer Research Institute de Lille, INSERM U837
Thérèse Commes: Institut de médecine régénératrice, Biothérapie et Institut de biologie computationnelle, INSERM U1040, Université de Montpellier
Eric Jourdan: Centre Hospitalier Universitaire de Nîmes, Université Montpellier-Nîmes
William Vainchenker: INSERM U1170, Gustave Roussy
Olivier Bernard: INSERM U1170, Gustave Roussy
Noemie Pata-Merci: INSERM US23, CNRS UMS3655, Gustave Roussy
Stéphanie Solier: INSERM U1170, Gustave Roussy
Velimir Gayevskiy: Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research
Marcel E. Dinger: Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research
Mark J. Cowley: Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research
Dorothée Selimoglu-Buet: INSERM U1170, Gustave Roussy
Vincent Meyer: Centre National de Génotypage
François Artiguenave: Centre National de Génotypage
Jean-François Deleuze: Centre National de Génotypage
Claude Preudhomme: Cancer Research Institute de Lille, INSERM U837
Michael R. Stratton: Cancer Genome Project, Wellcome Trust Sanger Institute
Ludmil B. Alexandrov: Cancer Genome Project, Wellcome Trust Sanger Institute
Eric Padron: Malignant hematology, H. Lee Moffitt Cancer Center
Seishi Ogawa: Kyoto University
Serge Koscielny: Gustave Roussy Cancer Center
Maria Figueroa: University of Michigan Medical School
Eric Solary: INSERM U1170, Gustave Roussy

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10767

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