Genetics of MDS

Abstract

Our knowledge about the genetics of myelodysplastic syndromes (MDS) and related myeloid disorders has been dramatically improved during the past decade, in which revolutionized sequencing technologies have played a major role. Through intensive efforts of sequencing of a large number of MDS genomes, a comprehensive registry of driver mutations recurrently found in a recognizable fraction of MDS patients has been revealed, and ongoing efforts are being made to clarify their impacts on clinical phenotype and prognosis, as well as their role in the pathogenesis of MDS. Among major mutational targets in MDS are the molecules involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. Showing substantial overlaps with driver mutations seen in acute myeloid leukemia (AML), as well as age-related clonal hematopoiesis in healthy individuals, these mutations are presumed to have a common clonal origin. Mutations are thought to be acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis, ultimately giving rise to MDS and subsequent transformation to AML in many patients. Significant correlations between mutations suggest the presence of functional interactions between mutations, which dictate disease progression. Mutations are frequently associated with specific disease phenotype, drug response, and clinical outcomes, and thus, it is essential to be familiar with MDS genetics for better management of patients. This review aims to provide a brief overview of the recent progresses in MDS genetics.

Figure 1.

Common driver alterations in MDS and other myeloid neoplasms. (A) Frequencies of major driver mutations and CNAs are plotted, combining data from 7 publications,^,,-, which include 1449 low- and 966 high-risk MDS, 46 MDS/MPN, 549 sAML, and 1540 primary AML (pAML) cases. Green bars indicate type I genes. (B) Odds ratios and their 95% confidence intervals (CIs) of frequencies of major driver mutations and CNAs between MDS (including MDS/MPN) and pAML are shown in forest plots.

Figure 2.

Correlations between driver mutations and CNAs in MDS. Significantly cooccurring and mutually exclusive alterations are shown in red and blue circles, respectively, on the basis of data from 6 published studies,^,,- where effect size and q-values are indicated by the size of circles and color gradient.

Figure 3.

Major functional pathways newly identified to be affected by somatic mutations. Major functional pathways newly identified as somatic alterations include DNA methylation (A), PRC2 and related genes (B), SFs (C), and the cohesion complex (D). For each panel, major targets of mutations are indicated with functional implications. 5hmc, 5′-hydroxymethylcytosine; 5mc, methylated cytosine; TCA, tricarboxylic acid.

Figure 4.

Functional interaction between TP53 and del(5q). (A) Effects of RPS14 haploinsufficiency on TP53 protein levels. In this model, haploinsufficient RPS14 results in an increase in ribosome-free RPL11, which by competing with TP53 for binding MDM2, an E3 ubiquitin ligase that also targets p53 for destruction, inhibits TP53 destruction in the proteasome, leading to an elevated TP53 level and an enhanced TP53-mediated apoptosis of erythroid progenitors.^, Protein levels corresponding to diploid and haploid status of RPS14 are indicated by solid and broken lines, respectively. (B) Effects of haploinsufficiency of CSKN2A on Wnt signaling and TP53 activation and their implication in the mechanism behind the high response of del(5q) clones to lenalidomide. Haploinsufficiency of RPS14 and CSKN2A induced TP53 activation, leading to enhanced apoptosis of del(5q) clones, while haploinsufficient CSKN2A results in the activation of Wnt signaling and cell proliferation. Apoptosis of del(5q) clones, particularly that induced by lenalidomide, critically depends on intact TP53, which explains the strong correlation between del(5q) and mutated TP53.