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Review

A Genetically-Informed Network Model of Myelodysplastic Syndrome: From Splicing Aberrations to Therapeutic Vulnerabilities

1
Translational-Transdisciplinary Research Center, Clinical Research Institute, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul 05278, Republic of Korea
2
Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02453, Republic of Korea
3
Division of Tourism & Wellness, Hankuk University of Foreign Studies, Yongin-si 17035, Republic of Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2025, 16(8), 928; https://doi.org/10.3390/genes16080928 (registering DOI)
Submission received: 7 July 2025 / Revised: 29 July 2025 / Accepted: 30 July 2025 / Published: 1 August 2025
(This article belongs to the Section Molecular Genetics and Genomics)

Abstract

Background/Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic disorder characterized by ineffective hematopoiesis and leukemic transformation risk. Current therapies show limited efficacy, with ~50% of patients failing hypomethylating agents. This review aims to synthesize recent discoveries through an integrated network model and examine translation into precision therapeutic approaches. Methods: We reviewed breakthrough discoveries from the past three years, analyzing single-cell multi-omics technologies, epitranscriptomics, stem cell architecture analysis, and precision medicine approaches. We examined cell-type-specific splicing aberrations, distinct stem cell architectures, epitranscriptomic modifications, and microenvironmental alterations in MDS pathogenesis. Results: Four interconnected mechanisms drive MDS: genetic alterations (splicing factor mutations), aberrant stem cell architecture (CMP-pattern vs. GMP-pattern), epitranscriptomic dysregulation involving pseudouridine-modified tRNA-derived fragments, and microenvironmental changes. Splicing aberrations show cell-type specificity, with SF3B1 mutations preferentially affecting erythroid lineages. Stem cell architectures predict therapeutic responses, with CMP-pattern MDS achieving superior venetoclax response rates (>70%) versus GMP-pattern MDS (<30%). Epitranscriptomic alterations provide independent prognostic information, while microenvironmental changes mediate treatment resistance. Conclusions: These advances represent a paradigm shift toward personalized MDS medicine, moving from single-biomarker to comprehensive molecular profiling guiding multi-target strategies. While challenges remain in standardizing molecular profiling and developing clinical decision algorithms, this systems-level understanding provides a foundation for precision oncology implementation and overcoming current therapeutic limitations.
Keywords: myelodysplastic syndrome; stem cell; splicing mutations; epitranscriptomics; precision medicine myelodysplastic syndrome; stem cell; splicing mutations; epitranscriptomics; precision medicine

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MDPI and ACS Style

Yu, S.; Kim, J.; Kim, M.S. A Genetically-Informed Network Model of Myelodysplastic Syndrome: From Splicing Aberrations to Therapeutic Vulnerabilities. Genes 2025, 16, 928. https://doi.org/10.3390/genes16080928

AMA Style

Yu S, Kim J, Kim MS. A Genetically-Informed Network Model of Myelodysplastic Syndrome: From Splicing Aberrations to Therapeutic Vulnerabilities. Genes. 2025; 16(8):928. https://doi.org/10.3390/genes16080928

Chicago/Turabian Style

Yu, Sanghyeon, Junghyun Kim, and Man S. Kim. 2025. "A Genetically-Informed Network Model of Myelodysplastic Syndrome: From Splicing Aberrations to Therapeutic Vulnerabilities" Genes 16, no. 8: 928. https://doi.org/10.3390/genes16080928

APA Style

Yu, S., Kim, J., & Kim, M. S. (2025). A Genetically-Informed Network Model of Myelodysplastic Syndrome: From Splicing Aberrations to Therapeutic Vulnerabilities. Genes, 16(8), 928. https://doi.org/10.3390/genes16080928

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