BackgroundIdiopathic non-clonal cytopenia (ICUS) and clonal cytopenia (CCUS) are common in the elderly population. While these entities have similar clinical presentations with peripheral blood cytopenia and less than 10% bone marrow dysplasia, their malignant potential is different and the biological relationship between these disorders and myeloid neoplasms such as myelodysplastic syndrome (MDS) is not fully understood. Aberrant DNA methylation has previously been described to play a vital role in MDS and acute myeloid leukemia (AML) pathogenesis. In addition, obesity confers a poorer prognosis in MDS with inferior overall survival and a higher rate of AML transformation. In this study, we measured DNA methylation of the promoter for the obesity-regulated geneLEP, encoding leptin, in hematopoietic cells from ICUS, CCUS and MDS patients and healthy controls. We investigated whetherLEPpromoter methylation is an early event in the development of myeloid neoplasms and whether it is associated with clinical outcome.ResultsWe found that blood cells of patients with ICUS, CCUS and MDS all have a significantly hypermethylatedLEPpromoter compared to healthy controls and thatLEPhypermethylation is associated with anemia, increased bone marrow blast percentage, and lower plasma leptin levels. MDS patients with a highLEPpromoter methylation have a higher risk of progression, shorter progression-free survival, and inferior overall survival. Furthermore,LEPpromoter methylation was an independent risk factor for the progression of MDS in a multivariate Cox regression analysis.ConclusionIn conclusion, hypermethylation of theLEPpromoter is an early and frequent event in myeloid neoplasms and is associated with a worse prognosis.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13148-023-01505-w.