Table 1.

Relevant mutations and noteworthy clinical consequences / targets in MDS.

Mutated Gene	Clinical Associations	Prognostic and Therapeutic Relevance
DNMT3A	-present in approximately 15% of MDS patients [8,16] -occur very early in disease evolution, most frequently as hotspot mutations in the R882 codon [8,16]	-linked to a higher risk of disease evolution to secondary AML, shorter survival in de novo MDS patients [67] and independently from MDS origin after HSCT [56]
TET2	-among the most frequently mutated genes in MDS (20-30%) [3,8]	-associated with increased response to hypomethylating agents, especially when present at high VAFs [42] -associated with shorter overall survival after HSCT [56]
ASXL1	-present in 10% − 20% of MDS patients [3,8] -associated with thrombocytopenia, increased bone marrow blasts, trisomy 8, intermediate-risk karyotype and mutations of RUNX1, EZH2, IDH1, IDH2, NRAS, JAK2, SETBP1, and SRSF2 [16,68]	-predict inferior outcome in MDS and CMML patients [16,68,69], including a shorter overall survival following HSCT [2]
Spliceosome gene mutations	-present in approximately 50% of MDS patients [8] -often represent early events with high VAFs at presentation [7,8]
SF3B1	-among the most frequently mutated genes in MDS (25% − 35% of patients) [3,8] -strong correlation with ring sideroblast phenotype and ineffective erythropoiesis -may be seen as a distinct nosologic entity [28]	-favorable prognosis [28] -high response rates to luspatercept [39] -K666N mutation may be associated with increased progression of MDS and distinct RNA splicing [70]
IDH1 and IDH2	-less common in MDS as compared to AML, affect <5% of MDS patients [42]	-prognostic impact in MDS are still up to debate, IDH1 mutations may have an adverse prognostic effect [71] -promising data from early clinical trials for IDH inhibitors enasidenib and ivosidenib [72]
RUNX1	-present in approximately 10% of patients [3,8] -linked to a higher incidence of thrombocytopenia [3]	-implied in disease progression and frequently found in secondary AML evolving from MDS [73] -associated with shorter survival following HSCT[2] -may lead to unresponsiveness to lenalidomide in del(5q) MDS [38]
NRAS, KRAS	-present in approximately 10% of MDS patients [3,8] -late, mostly subclonal events [32,33] -a cooperation between genes involved in the cohesin and RAS pathways was observed in 15% − 20% of MDS patients who evolved to secondary AML [32]	-adverse prognostic impact in lower risk MDS patients through a high transformation rate to secondary AML [32,33]
TP53	-present in 5% − 10% of MDS patients [3,8] -associate with reduced hemoglobin and platelet counts at MDS presentation [9] -closely linked to complex karyotypes	- provide a survival advantage during radio-chemotherapy and are enriched in individuals with therapy related MDS [13,14] - associate with dismal outcomes regardless of the applied therapy (HMA, allogeneic HSCT)[42,56] - adverse prognosis may depend on the mutation burden, allelic state and genomic context [74] - response to decitabine comparable to that of intermediate risk MDS patients [45] - loss of a mutation associates with improved outcome during disease course [65] - promising data from early clinical trials for - TP53 reactivator APR-246 in combination with azacitidine [75] - inhibitor of mitochondrial metabolism CPI-613 (Devimistat) - CD47 antibody Magrolimab
PPM1D	-present in <5% of MDS patients [3,8] -provide a survival advantage during radio-chemotherapy and are enriched in individuals with therapy related MDS [29,55]	-no significant impact on outcomes [55]
NPM1	-among the most frequently mutated genes in AML, but only found in around 2% of MDS cases [8,46]	-associated with an aggressive MDS phenotype and a high progression risk to AML [8,46], should be treated as AML whenever possible -similar to AML, appear to be stable during disease course [8,46] -intensive chemotherapy and HSCT seem to improve outcomes [46] -high activity of combination therapies of venetoclax and HMA in NPM1-mutated AML as well as in higher risk MDS [47] hint to a similarly high potential in MDS harboring NPM1 mutations