The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

Abstract

Genomic instability, microenvironmental aberrations, and somatic mutations contribute to the phenotype of myelodysplastic syndrome and the risk for transformation to AML. Genes involved in RNA splicing, DNA methylation, histone modification, the cohesin complex, transcription, DNA damage response pathway, signal transduction and other pathways constitute recurrent mutational targets in MDS. RNA-splicing and DNA methylation mutations seem to occur early and are reported as driver mutations in over 50% of MDS patients. The improved understanding of the molecular landscape of MDS has led to better disease and risk classification, leading to novel therapeutic opportunities. Based on these findings, novel agents are currently under preclinical and clinical development and expected to improve the clinical outcome of patients with MDS in the upcoming years. This review provides a comprehensive update of the normal gene function as well as the impact of mutations in the pathogenesis, deregulation, diagnosis, and prognosis of MDS, focuses on the most recent advances of the genetic basis of myelodysplastic syndromes and their clinical relevance, and the latest targeted therapeutic approaches including investigational and approved agents for MDS.

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

“…37 SETBP1 somatic mutations mainly involve 858-874 residues and could co-occur with À7/del(7q) abnormalities or with inv(16q10) (41%-54% of cases); however, their frequency in low-risk MDS is low, accounting for 2%-5% of cases, even though their presence conferees a poor prognosis. 31,43,44 In our study, SETBP1 variants, both pathogenic and VUS, were found in more than 50% of AML and MDS subjects, mostly localized between the AT hook 2 and the SET-binding domain. Moreover, MDS patients showed a higher genetic complexity compared to CCUS, as MDS subjects more frequently had two or more SETBP1 variants, especially…”

“…29,30 In MDS, genetic landscape differs between low-and high-risk MDS and between those myelodysplasias that rapidly progress to AML. 29,31,32 Accumulation of epigenetic modifications together with occurrence of TET2, IDH1, and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML. 7,29,33 Most frequent mutations involve SF3B1, TET2, ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, ZRSR2, STAG2, TP53, EZH2, CBL, JAK2, BCOR, IDH2, NRAS, and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities.…”

“…35 NRAS, ASXL1, RUNX1, and SETBP1 gene mutations are mutated only in less than 10% of MDS cases, even though are independent risk factors for inferior survival and the increased risk to AML transformation. 32,36 SETBP1, a 170-kDa nuclear protein that binds to SET protein, to AT-rich DNA regions-"AAAATAA/T" sequences, to promoter regions of genes involved in hemopoiesis, such as HOXA9, HOXA10, and RUNX1, 31,[37][38][39][40] to members of the KMT2A (lysine methyltransferase)-COMPASS (COMplex of Proteins ASsociated with SET1) family ultimately leading to methylation regulation of promoter regions of the HOX genes, 37 or to modified histones. 41,42 SETBP1 somatic mutations can occur in MDS and AML, causing upregulation of several genes, such as MECOM, a transcriptional regulator and oncoprotein involved in hematopoiesis, apoptosis, development, and cell differentiation and proliferation.…”

“…Accumulation of epigenetic modifications together with occurrence of TET2 , IDH1 , and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML 7,29,33 . Most frequent mutations involve SF3B1 , TET2 , ASXL1 , SRSF2 , DNMT3A , RUNX1 , U2AF1 , ZRSR2 , STAG2 , TP53 , EZH2 , CBL , JAK2 , BCOR , IDH2 , NRAS , and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities 6,29,31,34 . Overall, MDS show a higher genomic instability, as cytogenetics abnormalities are found in about 50% of patients, while whole exome sequencing can detect recurrent somatic mutations in 80%–90% of cases, usually six per exome in low‐risk MDS and nine in MDS with excess blasts 5 .…”

“…7,29,33 Most frequent mutations involve SF3B1, TET2, ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, ZRSR2, STAG2, TP53, EZH2, CBL, JAK2, BCOR, IDH2, NRAS, and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities. 6,29,31,34 Overall, MDS show a higher genomic instability, as cytogenetics abnormalities are found in about 50% of patients, while whole exome sequencing can detect recurrent somatic mutations in 80%-90% of cases, usually six per exome in low-risk MDS and nine in MDS with excess blasts. 5 In our study, when considered both known pathogenic mutations and VUS in AML-related genes identified by NGS, TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated in AML and MDS patients who had a median number of clones at diagnosis of four (range, 2-9) and three (range, 1-7), respectively, significantly higher than those observed in the control group (median, 2; range, 0-5; p < .0001).…”