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Unique epigenomic signatures identify biologically significant subtypes of MDS and predict response to azacytidine [RNA-Seq]

ABSTRACT: Myelodysplastic syndromes (MDS) are characterized by genetic mutations affecting epigenetic modifiers and aberrant DNA methylation. Although DNA methyltransferase inhibitors (DMTis) are used to treat MDS, response variability remains a challenge, with limited predictive markers. Through integration of comprehensive genomic, epigenomic, and transcriptomic data, we have gained valuable insights into the intricate interplay between genetic and epigenetic alterations in MDS. We identified both hypermethylated and hypomethylated regions in MDS compared to normal, with a significant presence of long-range gene regulatory interactions. Moreover, distinct molecular subtypes enriched for specific mutations were characterized, providing critical insights into MDS biology. Notably, we identified approximately 2,500 differentially methylated regions (DMRs) at baseline that distinguish responders from non-responders to AZA treatment. Leveraging these DMRs and their associated genes within the same topologically associating domains (TADs), we developed robust classifiers integrating DNA methylation (DNAme), gene expression (GE), mutations, Hemoglobin, age, Platelet, Blast BM Blast, and absolute neutrophil count (ANC) data, highlighting the potential of personalized treatment approaches for MDS patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281562 | GEO | 2026/07/27

REPOSITORIES: GEO

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Unique epigenomic signatures identify biologically significant subtypes of MDS and predict response to azacytidine [eRRBS]

Project description:Myelodysplastic syndromes (MDS) are characterized by genetic mutations affecting epigenetic modifiers and aberrant DNA methylation. Although DNA methyltransferase inhibitors (DMTis) are used to treat MDS, response variability remains a challenge, with limited predictive markers. Through integration of comprehensive genomic, epigenomic, and transcriptomic data, we have gained valuable insights into the intricate interplay between genetic and epigenetic alterations in MDS. We identified both hypermethylated and hypomethylated regions in MDS compared to normal, with a significant presence of long-range gene regulatory interactions. Moreover, distinct molecular subtypes enriched for specific mutations were characterized, providing critical insights into MDS biology. Notably, we identified approximately 2,500 differentially methylated regions (DMRs) at baseline that distinguish responders from non-responders to AZA treatment. Leveraging these DMRs and their associated genes within the same topologically associating domains (TADs), we developed robust classifiers integrating DNA methylation (DNAme), gene expression (GE), mutations, Hemoglobin, age, Platelet, Blast BM Blast, and absolute neutrophil count (ANC) data, highlighting the potential of personalized treatment approaches for MDS patients.

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Specific molecular signatures underlie response to decitabine in CMML [RNA-seq]

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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized variably by the presence of peripheral cytopenias, bone marrow hypercellularity and dysplastic changes in the bone marrow. While MDS patients have an increased risk of progression to acute myeloid leukemia (AML), most MDS patients actually succumb to progressive bone marrow failure. Amongst patients classified as low-risk MDS, different clinical evolutions have been observed, with some patients remaining relatively stable for long periods of time (herein, stable MDS), while others show more progressive disease, with worsening cytopenias, and often increased transfusion requirements (herein, progressive MDS). Current risk stratification strategies fail to distinguish these two groups at diagnosis. We report here that these distinct behaviors are encoded at the epigenetic level and that examining DNA methylation profiles of low-risk MDS patients captures underlying differences between the two different groups. In this study, we identified 356 differentially methylated regions (DMRs) between stable and progressive low-risk MDS at the time of diagnosis. The number of DMRs was almost doubled at the time of progression (681 follow-up DMRs), and this was accompanied by an increase in the local variability at specific methylation regions, and an increase in heterogeneity over time. These findings reveal previously unrecognized epigenetic heterogeneity in low-risk MDS patients and opens the possibility for using epigenetic differences to help improve risk-stratification at diagnosis.

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Homo sapiens

Project description:Mutations in DNA methylation pathway in MDS

| PRJNA381310 | ENA

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