Abstract
Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.
Highlights
Introduction published maps and institutional affilIn the World Health Organization (WHO) classification of myeloid neoplasms, myelodysplastic syndromes (MDS) are defined as clonal disorders of hematopoietic stem cell progenitors characterized by morphologic dysplasia, ineffective hematopoiesis, and increased risk of evolution into acute myeloid leukemia [1].Myelodysplastic syndromes (MDS) typically occur in elderly people
In patients affected with acute myeloid leukemia, a comparable frequency of STAG2 mutation rate has been reported, suggesting that altered cohesin function may have a role in myeloid leukemogenesis process [38]
While scientists are accumulating evidences to better understand the biological links among somatic mutations, diagnosis, prognosis, and therapeutic approaches in MDS
Summary
In the last years the advent of methods that improved genome/exome sequencing costs and throughputs allowed a detailed knowledge of the different mutational landscapes in MDS patients [8,9,10]. Using targeted-sequencing approaches, large MDS cohorts have been characterized by their mutational profiles and several recurrently mutated genes have been associated to myeloid neoplasms. By using this approach, up to 90% of patients have been found to have a somatic mutation in at least one gene, while the great majority of patients carried 2–4 mutations. MDS patients, whereas a long tail of 40–50 genes are mutated less frequently (
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