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RNA and Mitochondrial Reprogramming Associated with Azacytidine Treatment in Higher-Risk Myelodysplastic Syndromes: A
Theodoros Nikolopoulos1, Irene Dereki1, Vasiliki Chondrou1
1Biology Laboratory, School of Science and Technology, Hellenic Open University, 263 35 Patras, Greece.
Cancers
|July 28, 2026
Summary
Azacitidine (AZA) treatment in higher-risk myelodysplastic syndromes (HR-MDS) impacts RNA modifications and mitochondrial DNA, influencing patient response. Responders normalize metabolism, while non-responders show impaired adaptation.
Area of Science:
- * Hematology
- * Molecular Biology
- * Epigenetics
Background:
- * Azacitidine (AZA) is a hypomethylating agent used for higher-risk myelodysplastic syndromes (HR-MDS).
- * AZA's primary mechanism involves DNA demethylation and gene reactivation, but other molecular effects are emerging.
- * Understanding these additional effects is crucial for optimizing HR-MDS treatment.
Purpose of the Study:
- * To investigate comprehensive molecular changes induced by AZA in HR-MDS patients.
- * To correlate these molecular alterations with treatment response phenotypes (Responders vs. Non-Responders).
- * To identify novel biomarkers and therapeutic targets related to AZA efficacy.
Main Methods:
- * Liquid chromatography-mass spectrometry (LC-MS/MS) for quantifying RNA and DNA modifications.
- * Next-generation sequencing (NGS) for miRNA profiling.
- * Bioinformatic analyses including differential expression, gene set enrichment, and network analysis.
- * Digital PCR for assessing mitochondrial DNA (mtDNA) copy number.
Main Results:
- * Distinct miRNA expression patterns differentiated AZA Responders from Non-Responders.
- * Evaluated impact of RNA modifications (m6A, m5C, m1A, Gm, A→I editing) on treatment outcomes.
- * Observed changes in nuclear DNA/mtDNA methylation and reduced mtDNA copy number in response to AZA.
- * AZA Responders showed normalized glycolytic metabolism and enhanced ribosomal activity.
- * Non-Responders exhibited mtDNA depletion but failed to coordinate metabolic reprogramming.
Conclusions:
- * AZA induces significant epigenetic and metabolic reprogramming in HR-MDS.
- * miRNA profiles and RNA modifications are potential predictors of AZA response.
- * Metabolic adaptation, including normalized glycolysis and ribosomal activity, is key to AZA efficacy.
- * Reduced mtDNA content in Responders correlates with improved survival and suppressed malignant progression.
