A recent real-life retrospective study conducted by researchers in Italy has revealed potential prognostic markers for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), shedding light on the genetic factors underlying these hematological disorders.

The findings were published in the European Journal of Haematology.

The study identified several commonly mutated genes, with TET2 and SETBP1 being the most prevalent. TET2 and SETBP1 mutations were particularly prominent in MDS cases, affecting 79.2% and 66.7% of patients, respectively. Notably, patients with MDS exhibited a high level of genetic complexity, especially in relation to SETBP1 mutations.

Moreover, a subgroup of patients diagnosed with MDS or AML who displayed a more favorable prognosis presented with SETBP1 in its wild-type form or carried 2 or more simultaneous variants of uncertain clinical significance (VUS). Conversely, the presence of a single SETBP1 VUS was associated with a poorer prognosis, regardless of TET2 mutational status.

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Patients with pathogenic TET2 mutations and a single SETBP1 VUS displayed the poorest prognosis, with a median progression-free survival of 8.1 months.

“In our report, besides the small number of subjects enrolled, we proposed that genetic heterogeneity of clones in the bone marrow, regardless the known pathogenicity of variants, could underlie an ineffective hemopoiesis that might predispose to selection of clones harboring detrimental alterations, and resistance to chemotherapy and targeted therapies,” the researchers explained.

In addition to TET2 and SETBP1, the study identified ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 as commonly mutated genes.

The study identified 495 genetic alterations in 182 patients. Considering the AML-related genes, 347 variants were detected across AML, MDS, and clonal cytopenia of unknown significance (CCUS) groups, comprising 55.6% pathogenic variants and 44.4% VUS in patients with AML, 25.8% pathogenic variants and 74.2% VUS variants in subjects with MDS, and 22.5% pathogenic variants and 77.5% VUS variants in the group with CCUS.

The researchers conducted next-generation sequencing to identify somatic mutations in AML-related genes, aiming to elucidate the genetic mechanisms driving these malignancies.


Giudice V, Serio B, Errichiello S, et al. Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition. Eur J Haematol. Published online July 27, 2023. doi:10.1111/ejh.14069