Hecht Anna, Meyer Julia A, Jann Johann-Christoph, Sockel Katja, Giagounidis Aristoteles, Götze Katharina S, Letsch Anne, Haase Detlef, Schlenk Richard F, Haferlach Torsten, Schafhausen Philippe, Bug Gesine, Lübbert Michael, Thol Felicitas, Büsche Guntram, Schuler Esther, Nowak Verena, Obländer Julia, Fey Stephanie, Müller Nadine, Metzgeroth Georgia, Hofmann Wolf-Karsten, Germing Ulrich, Nolte Florian, Reinwald Mark, Nowak Daniel
Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Ann Hematol. 2021 Jun;100(6):1463-1471. doi: 10.1007/s00277-021-04492-1. Epub 2021 Apr 27.
Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.
伴有孤立性5号染色体长臂缺失的骨髓增生异常综合征（MDS del5q）是MDS的一种独特亚型，预后相当良好，对来那度胺治疗反应极佳。然而，仍有相当比例的患者对来那度胺无反应，甚至进展为急性髓系白血病（AML）。在本研究中，我们旨在调查全基因组DNA甲基化模式是否能够预测对来那度胺的反应。在德国MDS研究组的一项前瞻性多中心试验中，对n = 51例接受来那度胺统一治疗的MDS del5q患者进行了使用Illumina 450k甲基化芯片的全基因组DNA甲基化分析。为了研究来那度胺对DNA甲基化的潜在直接影响，分析了17对治疗前后的配对样本。我们的结果显示来那度胺对甲基化状态无相关影响。此外，治疗前的甲基化模式无法预测来那度胺反应。然而，甲基化聚类识别出一组总生存有较差趋势的患者。这些患者表现出几个有趣的靶基因的高甲基化，包括相关信号通路的基因，这可能表明对新治疗靶点的评估。
