Publications
Single-Cell DNA Methylation Analysis Uncovers Epigenetic Pathways in the Transformation of MDS to AML
Bueno-Costa A, Campillo-Marcos I, Casado-Peláez M, Yassine K, Noguera-Castells A, Zamora L, Xicoy B, Solé F, Mata C, Park J, Ganesan S, Della Porta MG, Ferrer G, Landau DA, Esteller M
Abstract
Using longitudinal bone marrow samples from five patients treated with azacitidine, this study applies single-cell DNA methylation profiling (Smart-RRBS) alongside Tapestri single-cell DNA and protein sequencing and 10x scRNA-seq to trace epigenetic evolution from myelodysplastic syndrome (MDS) through transformation to secondary acute myeloid leukemia (AML). Epimutation rate (PDR) and epigenetic heterogeneity (ΔPDR) increased progressively from healthy bone marrow through MDS to AML, with hypomethylating-agent responders and non-responders following distinct trajectories — including differential methylation at NPHP4 and downregulation of the FLT3 pathway in responders. Integrated multi-omic analysis showed responders lost their original malignant stem cell population after treatment but developed new clonal expansions during AML progression, while non-responders retained a stable, highly mutated stem cell pool throughout. The findings point to parallel co-evolution of multiple malignant stem cell populations rather than a single linear clonal path.