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


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.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors 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. ; Gayevskiy, V. ; Dinger, M. E. ; Cowley, M. J. ; Selimoglu-Buet, D. ; Meyer, V. ; Artiguenave, F. ; Deleuz
Publisher Name Nature Communications
Published Date 2016-01-01
Published Volume 7
Published Pages 10767
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version