The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications

Abstract

The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

Myelodysplasia Syndrome, Clonal Hematopoiesis and Cardiovascular Disease

“…Conventional chemoradiotherapy has been shown to cause a therapy- or treatment-related MDS (t-MDS/t-AML) in patients receiving treatment for other malignancies [ 9 , 10 , 11 ]. However, for the vast majority of patients, the cause of genetic abnormalities driving MDS is less understood [ 8 , 12 ].…”

“…Multiple genetic mutations and chromosomal abnormalities have been identified to cause MDS, and this diversity in driver mutations is responsible for the phenotypic heterogeneity observed in MDS ( Table 2 ). The genes that are most commonly mutated in MDS are involved in a variety of cellular regulatory functions, including DNA methylation, RNA-Splicing, DNA transcription, histone modification, signal transduction and the cohesion complex subunits [ 7 , 12 , 23 , 24 ]. Generally, mutations in epigenetic and RNA-splicing processes are termed “driver mutations”, as it is these mutations that tend to dictate what type of clone will outgrow and outcompete (also termed “clonal dominance”) [ 25 , 26 , 27 ].…”

“…The most common RNA-splicing genes mutated in MDS are SF3B1 , SRSF2 and U2-complex auxiliary factor 1 ( U2AF1 ); and zinc finger CCCH-type RNA binding motif and serine/arginine-rich 2 ( ZRSR2 ) [ 12 , 23 , 40 , 41 ]. The most common SF3B1 mutation observed is a lysine to glutamic acid substitution at codon 700 (K700E); however, mutations in the conserved amino acids 622, 625, 662 and 666 are also documented to a lesser degree [ 23 , 42 , 43 ].…”

“…Additionally, several inherited disorders increase the risk of MDS development [ 49 ]. These include Fanconi anemia ( FANC genes), Shwachman–Diamond syndrome ( SBDS gene), Li-Fraumeni Syndrome ( TP53 ), Diamond–Blackfan anemia ( GATA1/RPS19 ), Dyskeratosis congenita and other telomerase complex disorders to name a few [ 7 , 12 , 49 ]. Patients with Tatton–Brown–Rahmann Syndrome caused by germline mutations in DNMT3a may also be at an increased risk of developing MDS/AML; however, this syndrome was only recently described, and there is limited longitudinal data, as all of the patients are still very young [ 51 , 52 ].…”

“…Additionally, genetic mutations involved in DNA repair or DNA methylation can cause chromosomal instability and consequently also confer a chromosomal defect. Indeed, unbalanced DNA methylation changes can induce chromosomal rearrangements and are frequently observed in a plethora of oncogenic diseases [ 12 , 53 ].…”