Merlevede Jane, Droin Nathalie, Qin Tingting, Meldi Kristen, Yoshida Kenichi, Morabito Margot, Chautard Emilie, Auboeuf Didier, Fenaux Pierre, Braun Thorsten, Itzykson Raphael, de Botton Stéphane, Quesnel Bruno, Commes Thérèse, Jourdan Eric, Vainchenker William, Bernard Olivier, Pata-Merci Noemie, Solier Stéphanie, Gayevskiy Velimir, Dinger Marcel E, Cowley Mark J, Selimoglu-Buet Dorothée, Meyer Vincent, Artiguenave François, Deleuze Jean-François, Preudhomme Claude, Stratton Michael R, Alexandrov Ludmil B, Padron Eric, Ogawa Seishi, Koscielny Serge, Figueroa Maria, Solary Eric
INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.
Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France.
Nat Commun. 2016 Feb 24;7:10767. doi: 10.1038/ncomms10767.
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.
胞嘧啶类似物阿扎胞苷和5-氮杂-2'-脱氧胞苷（地西他滨）常用于治疗骨髓增生异常综合征，无论是否伴有骨髓增殖成分。目前尚不清楚对这些去甲基化药物的反应是由细胞毒性作用还是表观遗传效应引起的。在本研究中，我们在慢性粒单核细胞白血病中解决了这个问题。我们结合全外显子组测序和全基因组测序，对这些肿瘤的突变图谱进行了全面分析。我们在分选的单核细胞DNA编码序列中平均鉴定出14±5个体细胞突变以及三种突变过程的特征。连续测序表明，对去甲基化药物的反应与DNA甲基化和基因表达的变化有关，而突变等位基因负担没有任何降低，也没有阻止新的基因改变的发生。我们的研究结果表明，胞嘧啶类似物可恢复平衡的造血功能，而不会减小突变克隆的大小，这表明主要是表观遗传效应。
