{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:58:20Z","timestamp":1790708300328,"version":"4.1.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Blood Cancer United","award":["3-5719"],"award-info":[{"award-number":["3-5719"]}],"id":[{"id":"https:\/\/ror.org\/0055acf80","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Blood Cancer United","award":["7028-22"],"award-info":[{"award-number":["7028-22"]}],"id":[{"id":"https:\/\/ror.org\/0055acf80","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NHLBI","award":["R01HL126947"],"award-info":[{"award-number":["R01HL126947"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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 \u2264 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.<\/jats:p>","DOI":"10.1172\/jci208317","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:59:41Z","timestamp":1790704781000},"source":"Crossref","is-referenced-by-count":0,"title":["DNA methylation status at diagnosis in MDS predicts response to azacitidine"],"prefix":"10.1172","author":[{"given":"Qin","family":"Yang","sequence":"first","affiliation":[{"name":"Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-8936","authenticated-orcid":true,"given":"Miguel","family":"Torres-Martin","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Brogi","sequence":"additional","affiliation":[{"name":"Hematology, University of Florence AOU Careggi, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Casalin","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical and Neuromotor Sciences, Universit\u00e0 di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Ceneri","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical and Neuromotor Sciences, Universit\u00e0 di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Halene","sequence":"additional","affiliation":[{"name":"Dept. of Internal Medicine, Yale University School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"DeZern","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde Y.","family":"Follo","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical and Neuromotor Sciences, Universit\u00e0 di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Finelli","sequence":"additional","affiliation":[{"name":"Dept. of Experimental, Diagnostic and Specialty Medicine, Universit\u00e0 di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerald P.","family":"Radich","sequence":"additional","affiliation":[{"name":"Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Rauh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Bejar","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikkael A.","family":"Sekeres","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Santini","sequence":"additional","affiliation":[{"name":"Hematology, University of Florence AOU Careggi, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Dept. of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,29]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/208317\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:59:42Z","timestamp":1790704782000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/208317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":0,"alternative-id":["10.1172\/JCI208317"],"URL":"https:\/\/doi.org\/10.1172\/jci208317","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}