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Genetic abnormalities and pathophysiology of MDS

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Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies characterized by peripheral blood cytopenia and dishematopoiesis and frequently progress to acute myeloid leukemia. Genetic defects play a major role in pathogenesis of MDS, including cytogenetic abnormalities, gene mutations, and abnormal gene expression. Chromosomal abnormalities have been detected in approximately 50–60% of MDS patients, including the deletions of chromosome 5q and 7q, trisomy 8, and complex karyotypes. Newer genomic technologies, such as single-nucleotide polymorphism array and next-generation sequencing, revealed the heterozygous deletions resulting in haploinsufficient gene expression (e.g., CSNK1A1, DDX41 on chromosome 5, CUX1, LUC7L2, EZH2 on chromosome 7) involved in the pathogenesis of MDS. In addition, recurrent somatic mutations in more than 50 genes have been identified in 80–90% of MDS. The most recurrent genetic mutations are involved in the RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2, LUC7L2, DDX41) and epigenetic modifications, such as histone modification (e.g., ASXL1, EZH2) and DNA methylation (e.g., TET2, DNMT3A, IDH1/IDH2). TP53 mutation is associated with aggressive disease and frequently coincides with deletion of chromosome 5q. This review summarizes the recent progress in molecular pathogenesis of MDS. A better understanding of the specific subgroups of MDS patients will also aid in the development of new therapeutic approach for MDS.

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Acknowledgements

First and foremost, the author would like to thank Professor Jaroslaw P. Maciejewski, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH and Professor Hideki Makishima, Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University. This work was supported by JSPS KAKENHI Grant Number JP 16K09844 and The Naito Foundation Naito Foundation.

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  1. Division of Hematology and Oncology, University of Fukui, Matsuokashimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan

    Naoko Hosono

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Hosono, N. Genetic abnormalities and pathophysiology of MDS. Int J Clin Oncol 24, 885–892 (2019). https://doi.org/10.1007/s10147-019-01462-6

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