Journal Article

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

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

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208/176/1988 / 631/208/68 / 631/67/1059/99 / 631/67/1990/283/1896 / Aged / Aged, 80 and over / Aged, 80 and over Alleles Antimetabolites, Antineoplastic / pharmacology Antimetabolites, Antineoplastic / therapeutic use Azacitidine / analogs & derivatives Azacitidine / pharmacology Azacitidine / therapeutic use Cell Survival / drug effects DNA Methylation / drug effects Decitabine Epigenesis, Genetic / drug effects Female Gene Expression Regulation, Neoplastic / drug effects HEK293 Cells High-Throughput Nucleotide Sequencing Humans Leukemia, Myelomonocytic, Chronic / drug therapy Leukemia, Myelomonocytic, Chronic / genetics Male Middle Aged Mutation / Alleles / Antimetabolites, Antineoplastic - pharmacology / Antimetabolites, Antineoplastic - therapeutic use / Azacitidine - analogs & derivatives / Azacitidine - pharmacology / Azacitidine - therapeutic use / BASIC BIOLOGICAL SCIENCES / biological sciences / cancer / Cell Survival - drug effects / Deoxyribonucleic acid / DNA / DNA Methylation - drug effects / Epigenesis, Genetic - drug effects / Female / Gene Expression Regulation, Neoplastic - drug effects / genetics / HEK293 Cells / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / Leukemia / Leukemia, Myelomonocytic, Chronic - drug therapy / Leukemia, Myelomonocytic, Chronic - genetics / Life Sciences / Male / Middle Aged / multidisciplinary / Mutation / Science / Science (multidisciplinary) / Sequence Analysis, DNA / Sequence Analysis, RNA