Rombaut David, Sandmann Sarah, Tekath Tobias, Crouch Simon, de Graaf Aniek O, Smith Alexandra, Painter Daniel, Kosmider Olivier, Tobiasson Magnus, Lennartsson Andreas, van der Reijden Bert A, Park Sophie, D'Aveni Maud, Slama Borhane, Clappier Emmanuelle, Fenaux Pierre, Adès Lionel, van de Loosdrecht Arjan, Langemeijer Saskia, Symeonidis Argiris, Čermák Jaroslav, Preudhomme Claude, Savic Aleksandar, Germing Ulrich, Stauder Reinhard, Bowen David, van Marrewijk Corine, Bernard Elsa, de Witte Theo, Varghese Julian, Hellström-Lindberg Eva, Dugas Martin, Martens Joost, Malcovati Luca, Jansen Joop H, Fontenay Michaela
Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104 Assistance Publique-Hôpitaux de Paris.Centre, Laboratory of Hematology, Hôpital Cochin Paris France.
Institute of Medical Informatics University of Münster Münster Germany.
Hemasphere. 2025 Jan 22;9(1):e70073. doi: 10.1002/hem3.70073. eCollection 2025 Jan.
Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival ( < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.
低危（LR）骨髓增生异常综合征（MDS）是由多种基因（包括表观遗传调节因子）中的体细胞突变积累引起的异质性造血干细胞和祖细胞疾病，这些突变可能产生趋同的DNA甲基化模式，驱动特定的基因表达谱。基因组、表观基因组和转录组分析的整合有可能根据病理生理机制突出不同的LR-MDS类别。我们对来自EUMDS注册中心（ClinicalTrials.gov.NCT00600860）的一大群初诊时未经治疗的LR-MDS患者进行了体细胞突变和DNA甲基化的综合研究。无监督聚类分析基于基因谱确定了六个聚类，基于全基因组甲基化谱将其浓缩为四个聚类，两种聚类模式之间有显著重叠。这四个甲基化聚类显示出不同的临床和遗传特征以及不同的甲基化格局。所有聚类均共享富含ETS和bZIP（C/EBP）转录因子家族结合基序的高甲基化增强子，这些家族参与髓系细胞分化的调控。相比之下，一个聚集早期白血病进展患者的聚类表现出特定的高甲基化启动子模式，与其他聚类不同的是，AP-1复合体成员FOS/FOSL2上调，且其在靶基因增强子处的结合基序没有高甲基化，这与白血病起始相关。在低危IPSS-M的MDS患者中，该聚类的总生存期显著较差（<0.0001）。我们的研究表明，LR-MDS早期的遗传和DNA甲基化特征可能优化风险分层，从而为早期治疗干预提供框架。
