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Clinical Research and Public HealthIn-Press PreviewGeneticsHematology Open Access | 10.1172/JCI208317

DNA methylation status at diagnosis in MDS predicts response to azacitidine

Qin Yang,1 Miguel Torres-Martin,2 Masataka Taguchi,1 Alice Brogi,3 Irene Casalin,4 Eleonora Ceneri,4 Stephanie Halene,5 Amy E. DeZern,6 Elizabeth A. Griffiths,7 Matilde Y. Follo,4 Carlo Finelli,8 Jerald P. Radich,9 Michael J. Rauh,10 Rafael Bejar,11 Mikkael A. Sekeres,2 Valeria Santini,3 and Maria E. Figueroa1

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Yang, Q. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Torres-Martin, M. in: PubMed | Google Scholar |

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Taguchi, M. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Brogi, A. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Casalin, I. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Ceneri, E. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Halene, S. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by DeZern, A. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Griffiths, E. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Follo, M. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Finelli, C. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Radich, J. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Rauh, M. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Bejar, R. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Sekeres, M. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Santini, V. in: PubMed | Google Scholar

1Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America

2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

3Hematology, University of Florence AOU Careggi, Florence, Italy

4Dept. of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

5Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America

6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America

7Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America

8Dept. of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Bologna, Italy

9Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America

10Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

11Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America

Find articles by Figueroa, M. in: PubMed | Google Scholar

Published September 29, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI208317.
Copyright © 2026, Yang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 29, 2026 - Version history
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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.

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