title: Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents.
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.
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Jane
authors.initials: J
authors.lastname: Merlevede
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.|INSERM US23, CNRS UMS3655, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Meldi
authors.affiliation: Department of Pathology and Tumour Biology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Margot
authors.initials: M
authors.lastname: Morabito
authors.affiliation: Université Lyon 1, UMR CNRS 5558, Université Claude Bernard, 16 rue Raphael Dubois, Lyon 69100, France.
authors.forename: Emilie
authors.identifier: http://orcid.org/0000-0003-1456-5347
authors.initials: E
authors.lastname: Chautard
authors.affiliation: Centre Léon Bérard, INSERM U1052, CNRS UMR5286, 8 Prom. Léa et Napoléon Bullukian, 69008 Lyon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
authors.affiliation: Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, 125 Rue de Stalingrad, 93000 Bobigny, France.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.affiliation: Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Itzykson
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.affiliation: Cancer Research Institute de Lille, INSERM U837, 1 Place de Verdun, 59000 Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.affiliation: Institut de médecine régénératrice, Biothérapie et Institut de biologie computationnelle, INSERM U1040, Université de Montpellier, 80 avenue Augustin Fliche. 34295 Montpellier, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Commes
authors.affiliation: Department of Hematology, Centre Hospitalier Universitaire de Nîmes, Université Montpellier-Nîmes, 4 Rue du Professeur Robert Debré, 30029 Nîmes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bernard
authors.affiliation: INSERM US23, CNRS UMS3655, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Noemie
authors.initials: N
authors.lastname: Pata-Merci
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Solier
authors.affiliation: Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst New South Wales 2010, Australia.
authors.forename: Velimir
authors.initials: V
authors.lastname: Gayevskiy
authors.affiliation: Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst New South Wales 2010, Australia.
authors.forename: Marcel E
authors.identifier: http://orcid.org/0000-0003-4423-934X
authors.initials: ME
authors.lastname: Dinger
authors.affiliation: Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst New South Wales 2010, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Selimoglu-Buet
authors.affiliation: Centre National de Génotypage, 2 rue Gaston Crémieux CP 5721, 91 057 Evry, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Meyer
authors.affiliation: Centre National de Génotypage, 2 rue Gaston Crémieux CP 5721, 91 057 Evry, France.
authors.forename: François
authors.initials: F
authors.lastname: Artiguenave
authors.affiliation: Centre National de Génotypage, 2 rue Gaston Crémieux CP 5721, 91 057 Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Cancer Research Institute de Lille, INSERM U837, 1 Place de Verdun, 59000 Lille, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545, USA.|Center for Nonlinear Studies, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545, USA.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Department of Hematology, Malignant hematology, H. Lee Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, Florida 33612, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Padron
authors.affiliation: Department of Pathology and Tumour Biology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Biostatistics, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Koscielny
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Figueroa
authors.affiliation: INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.|Department of Hematology, Faculty of Medicine, University Paris-Sud, 63 Rue Gabriel Péri, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine