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

Jane Merlevede 1, 2 Nathalie Droin 1, 2, 3 Tingting Qin 4 Kristen Meldi 5 Kenichi Yoshida 6, 7 Margot Morabito 2, 1 Emilie Chautard 8 Didier Auboeuf 9 Pierre Fenaux 10 Thorsten Braun 11 Raphaël Itzykson 1, 10 Stéphane de Botton 12 Bruno Quesnel 13 T. Commes 14 Eric Jourdan 15 William Vainchenker 2 Olivier Bernard 16 Noémie Pata-Merci 3 Stéphanie Solier 17, 16 Velimir Gayevskiy 18 Marcel E Dinger 18 Mark Cowley 18 Dorothée Selimoglu-Buet 16 Vincent Meyer 19 François Artiguenave 19 Jean-François Deleuze 19 Claude Preudhomme 20 Michael Stratton 21 Ludmil B. Alexandrov 21, 22 Eric Padron 23 Seishi Ogawa 7 Serge Koscielny 24 Maria Figueroa 4 Eric Solary 2
1 Hématopoïèse normale et pathologique
2 Dynamo - Dynamique moléculaire de la transformation hématopoïétique
3 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
4 University of Michigan Medical School [Ann Arbor]
5 School of Information, University of Michigan
6 Department of Molecular Diagnosis
7 Kyoto University [Kyoto]
8 LBBE - Laboratoire de Biométrie et Biologie Evolutive - UMR 5558
9 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
10 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
11 Hôpital Avicenne [AP-HP]
12 Département d'hématologie [Gustave Roussy]
13 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
14 Cellules souches normales et cancéreuses
15 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
16 U1170 Inserm - Hématopoïèse normale et pathologique
17 IGR - Institut Gustave Roussy
18 Garvan Institute of Medical Research [Darlinghurst, Australia]
19 CNG - Centre National de Génotypage
20 Service d'Hématologie Cellulaire [Lille]
21 The Wellcome Trust Sanger Institute [Cambridge]
22 LANL - Los Alamos National Laboratory
23 H. Lee Moffitt Cancer Center and Research Institute
24 SBE - Service de biostatistique et d'épidémiologie
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.
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https://hal.archives-ouvertes.fr/hal-03130526
Contributor : Odile Hennaut <>
Submitted on : Wednesday, February 3, 2021 - 4:17:44 PM
Last modification on : Wednesday, February 24, 2021 - 11:26:05 AM

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Jane Merlevede, Nathalie Droin, Tingting Qin, Kristen Meldi, Kenichi Yoshida, et al.. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nature Communications, Nature Publishing Group, 2016, 7 (1), ⟨10.1038/ncomms10767⟩. ⟨hal-03130526⟩

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