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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
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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Submitted on : Wednesday, February 3, 2021 - 4:17:44 PM
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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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