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Nat Commun. 2016 Feb 24;7:10767. doi: 10.1038/ncomms10767.

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

Author information

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.

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.

PMID:
26908133
PMCID:
PMC4770084
DOI:
10.1038/ncomms10767
[Indexed for MEDLINE]
Free PMC Article

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