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

Eur J Haematol. 2023 Nov;111(5):729-741. doi: 10.1111/ejh.14069. Epub 2023 Jul 27.


Background: Splicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real-life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia-related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML.

Methods: A total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML-related genes by next-generation sequencing.

Results: We showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild-type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status.

Conclusions: In conclusions, we linked both pathogenic and VUS variants in AML-related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results.

Keywords: acute myeloid leukemia; clonal hematopoiesis; myelodysplastic syndromes; pathogenic mutations; variants of uncertain significance.

MeSH terms

  • Clinical Relevance
  • Disease Susceptibility
  • Humans
  • Leukemia, Myeloid, Acute* / diagnosis
  • Leukemia, Myeloid, Acute* / genetics
  • Mutation
  • Myelodysplastic Syndromes* / diagnosis
  • Myelodysplastic Syndromes* / genetics
  • Prognosis
  • Prospective Studies
  • Retrospective Studies