Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q)

Anna Hecht,Katja Sockel,Guntram Büsche ,Mark Reinwald,Stéphanie Fey ,Richard F Schlenk,Katharina Götze ,Aristoteles Giagounidis,Anne Letsch,Esther Schuler,Michael Lübbert ,Wolf‐Karsten Hofmann ,Verena Nowak,Florian Nolte,Torsten Haferlach,Johann-Christoph Jann,Detlef Haase,Julia Meyer ,Julia Obländer ,Philippe Schafhausen,Gesine Bug,Felicitas Thol,Nadine Müller ,Georgia Metzgeroth,Ulrich Germing,Daniel Nowak

doi:10.1007/s00277-021-04492-1

Abstract

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.

Highlights

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a biologically and phenotypically distinct subtype of MDS
Genome-wide methylation patterns are stable during lenalidomide treatment
To elucidate whether lenalidomide treatment leads to changes in global methylation patterns, we generated Illumina 450k methylation data using bone marrow mononuclear cells from 17 patients of the LE-MON-5 study at the start of the study and 4–6 months after the start of lenalidomide treatment

Summary

Introduction

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a biologically and phenotypically distinct subtype of MDS. It is often characterized by severe macrocytic anemia and normal, or elevated, platelet counts. Several large studies demonstrated an excellent response to the immunomodulatory drug lenalidomide for patients with MDS del5q [2,3,4]. Progression to AML was observed in 15% of patients This was not predictable by any clinical marker and raises the question of feasibility for potential combination therapies in addition to lenalidomide alone [5]

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Conclusion