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

Jane Merlevede, Nathalie Droin, Tingting Qin, Kristen Meldi, Kenichi Yoshida, Margot Morabito, Emilie Chautard, Didier Auboeuf, Pierre Fenaux, Thorsten Braun, Raphael Itzykson, Stéphane De Botton, Bruno Quesnel, Thérèse Commes, Eric Jourdan, William Vainchenker, Olivier Bernard, Noemie Pata-Merci, Stéphanie Solier, Velimir GayevskiyMarcel E. Dinger, Mark J. Cowley, Dorothée Selimoglu-Buet, Vincent Meyer, François Artiguenave, Jean François Deleuze, Claude Preudhomme, Michael R. Stratton, Ludmil B. Alexandrov, Eric Padron, Seishi Ogawa, Serge Koscielny, Maria Figueroa, Eric Solary

Research output: Contribution to journalArticle

99 Scopus citations

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.

Original languageEnglish (US)
Article number10767
JournalNature Communications
Volume7
DOIs
StatePublished - Feb 24 2016
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Merlevede, J., Droin, N., Qin, T., Meldi, K., Yoshida, K., Morabito, M., Chautard, E., Auboeuf, D., Fenaux, P., Braun, T., Itzykson, R., De Botton, S., Quesnel, B., Commes, T., Jourdan, E., Vainchenker, W., Bernard, O., Pata-Merci, N., Solier, S., ... Solary, E. (2016). Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nature Communications, 7, [10767]. https://doi.org/10.1038/ncomms10767