TY - JOUR
T1 - Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
AU - Merlevede, Jane
AU - Droin, Nathalie
AU - Qin, Tingting
AU - Meldi, Kristen
AU - Yoshida, Kenichi
AU - Morabito, Margot
AU - Chautard, Emilie
AU - Auboeuf, Didier
AU - Fenaux, Pierre
AU - Braun, Thorsten
AU - Itzykson, Raphael
AU - De Botton, Stéphane
AU - Quesnel, Bruno
AU - Commes, Thérèse
AU - Jourdan, Eric
AU - Vainchenker, William
AU - Bernard, Olivier
AU - Pata-Merci, Noemie
AU - Solier, Stéphanie
AU - Gayevskiy, Velimir
AU - Dinger, Marcel E.
AU - Cowley, Mark J.
AU - Selimoglu-Buet, Dorothée
AU - Meyer, Vincent
AU - Artiguenave, François
AU - Deleuze, Jean François
AU - Preudhomme, Claude
AU - Stratton, Michael R.
AU - Alexandrov, Ludmil B.
AU - Padron, Eric
AU - Ogawa, Seishi
AU - Koscielny, Serge
AU - Figueroa, Maria
AU - Solary, Eric
N1 - Funding Information:
This programme was supported by grants from Ligue Nationale Contre le Cancer (équipe labellisée), Institut National du Cancer (INCa PLBIO, SIRIC SOCRATE), Institut National du Cancer and Direction Générale de l’Offre de Soins (PHRC-K 2011-182), Agence Nationale de la Recherche (Molecular Medicine in Oncology; Paris Alliance Cancer Research Institute: France Génomique National programs funded by ‘Investissements d’avenir’). J.M. was supported by the Fondation pour la Recherche Médicale (FDT20140931007).
PY - 2016/2/24
Y1 - 2016/2/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84959419471&partnerID=8YFLogxK
U2 - 10.1038/ncomms10767
DO - 10.1038/ncomms10767
M3 - Article
C2 - 26908133
AN - SCOPUS:84959419471
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 10767
ER -