DNA methylation status at diagnosis in MDS predicts response to azacitidine

Background. Myelodysplastic syndromes (MDS) are characterized by aberrant DNA methylation, and mutations in epigenetic modifiers are frequently found in these patients. Although DNA methyltransferase inhibitors (DNMTi) are used to treat MDS, response variability remains a challenge in the clinic, with limited predictive markers. Methods. We integrated genomic, epigenomic, and transcriptomic analyses of 98 MDS patients. Patients were classified into epigenetic subtypes via hierarchical clustering. Random forest classifiers were developed and validated using internal stratified testing and an independent external cohort to predict AZA response. Results. MDS is characterized by widespread DNA hypomethylation affecting distal regulatory elements. We identified seven epigenetic clusters correlated with distinct molecular drivers. Notably, Cluster VI exhibited low mutational burden but a high AZA response rate of 71% (P ≤ 0.01). While transcriptional profiles alone failed to distinguish responders, a DNAme-based classifier achieved an area under the curve (AUC) of 0.82. An integrative model combining DNAme, gene expression, mutations, and clinical parameters achieved an AUC of 0.93 in internal validation and 0.88 in the external cohort. Conclusion. Epigenetic signatures at distal genomic elements provide superior predictive power for AZA response compared to promoter-centric or transcriptional analyses. These findings establish a robust framework for personalized treatment strategies in MDS.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2026-09-29
DOI
https://doi.org/10.1172/jci208317
Primary Topic
Acute Myeloid Leukemia Research
Type
article
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0.00
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article

DNA methylation status at diagnosis in MDS predicts response to azacitidine

María E. Figueroa, Irene Casalin, Amy Elizabeth Dezern, Matilde Y. Follo et al.
Journal of Clinical Investigation
Acute Myeloid Leukemia Research
article

DNA methylation status at diagnosis in MDS predicts response to azacitidine

María E. Figueroa, Irene Casalin, Amy Elizabeth Dezern, Matilde Y. Follo, Stephanie Halene, Mikkael Aaron Sekeres, Alice Brogi, Elizabeth A. Griffiths, Michael J. Rauh, Masataka Taguchi, Carlo Finelli, Miguel Torres‐Martín, Jerald P. Radich, Valeria Santini, Eleonora Ceneri, Rafael Bejar, Qin Yang
article en

Abstract

Background. Myelodysplastic syndromes (MDS) are characterized by aberrant DNA methylation, and mutations in epigenetic modifiers are frequently found in these patients. Although DNA methyltransferase inhibitors (DNMTi) are used to treat MDS, response variability remains a challenge in the clinic, with limited predictive markers. Methods. We integrated genomic, epigenomic, and transcriptomic analyses of 98 MDS patients. Patients were classified into epigenetic subtypes via hierarchical clustering. Random forest classifiers were developed and validated using internal stratified testing and an independent external cohort to predict AZA response. Results. MDS is characterized by widespread DNA hypomethylation affecting distal regulatory elements. We identified seven epigenetic clusters correlated with distinct molecular drivers. Notably, Cluster VI exhibited low mutational burden but a high AZA response rate of 71% (P ≤ 0.01). While transcriptional profiles alone failed to distinguish responders, a DNAme-based classifier achieved an area under the curve (AUC) of 0.82. An integrative model combining DNAme, gene expression, mutations, and clinical parameters achieved an AUC of 0.93 in internal validation and 0.88 in the external cohort. Conclusion. Epigenetic signatures at distal genomic elements provide superior predictive power for AZA response compared to promoter-centric or transcriptional analyses. These findings establish a robust framework for personalized treatment strategies in MDS.

Journal of Clinical Investigation
Roswell Park Comprehensive Cancer Center (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Johns Hopkins University (US), University of Miami (US), University of San Diego (US), Queen's University (CA), Johns Hopkins Medicine (US), Yale University (US), Fred Hutch Cancer Center (US), Azienda Ospedaliero-Universitaria Careggi (IT), Sylvester Comprehensive Cancer Center (US), Sidney Kimmel Comprehensive Cancer Center (US), University of Bologna (IT)
Life in Land
Openalex Percentile: Top 11%
Acute Myeloid Leukemia Research
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