Jane Merlevede 1 , 2 , Nathalie Droin 1 , 2 , 3 , Tingting Qin 4 , Kristen Meldi 4 , Kenichi Yoshida 5 , Margot Morabito 1 , 2 , Emilie Chautard 6 , Didier Auboeuf 7 , Pierre Fenaux 8 , Thorsten Braun 9 , Raphael Itzykson 8 , Stéphane de Botton 1 , 2 , Bruno Quesnel 10 , Thérèse Commes 11 , Eric Jourdan 12 , William Vainchenker 1 , 2 , Olivier Bernard 1 , 2 , Noemie Pata-Merci 3 , Stéphanie Solier 1 , 2 , Velimir Gayevskiy 13 , Marcel E. Dinger 13 , Mark J. Cowley 13 , Dorothée Selimoglu-Buet 1 , 2 , Vincent Meyer 14 , François Artiguenave 14 , Jean-François Deleuze 14 , Claude Preudhomme 10 , Michael R. Stratton 15 , Ludmil B. Alexandrov 15 , 16 , 17 , Eric Padron 18 , Seishi Ogawa 5 , Serge Koscielny 19 , Maria Figueroa 4 , Eric Solary a , 1 , 2 , 20
24 February 2016
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.
Chronic myelomonocytic leukaemia is treated with agents that modify DNA methylation but whether they have direct cytotoxic effects is unclear. Here, the authors show that cells from treated patients show marked methylation changes without altered somatic mutation burden, suggesting that cytotoxicity is not a major factor in therapeutic efficacy.