Single-cell DNA methylation analysis uncovers epigenetic pathways in the transformation of MDS to AML

作者：Alberto Bueno-Costa, Ignacio Campillo‐Marcos, Marta Casado-Peláez, Karim Yassine, Aleix Noguera‐Castells, Lurdes Zamora, Blanca Xicoy, Françesc Solé, Caterina Mata, Jane Park, Saravanan Ganesan, Matteo Giovanni Della Porta, Gerardo Ferrer, Dan A. Landau, Manel Esteller · 发表于：Leukemia · 年份：2026 · DOI：10.1038/s41375-026-03015-z · 研究领域：Acute Myeloid Leukemia Research、Epigenetics and DNA Methylation、Cancer Genomics and Diagnostics

Acute myeloid leukemia (AML) can arise from an antecedent myelodysplastic neoplasm (MDS) [ 1 ] despite the treatment with hypomethylating agents (HMA). This secondary AML (sAML) is associated with resistance to therapies and shortened survival [ 1 ]. Both MDS and AML undergo aberrations in DNA methylation [ 2 , 3 , 4 ], but the MDS to AML transformation has been mostly studied at the genetic level [ 5 ]. We wondered if uncovering the single-cell DNA methylation (scDNA-Met) ecosystem could yield relevant clues to understand the biology of these aggressive sAMLs in a similar manner that has been shown for hematopoietic stem cell differentiation during aging [ 6 ]. We dissected in a longitudinal manner the epigenetic phylogeny of patients with MDS at diagnosis (Dx), at the end of HMA therapy (Post-HMA), and upon the rise of sAML using Smart-RRBS (reduced representation bisulfite sequencing) [ 7 , 8 ], which allows single-cell DNA methylation resolution, with complementary studies of RNA, DNA mutational status, and protein expression also at the single-cell level. Since the origin of MDS and AML is mostly confined within the hematopoietic stem and progenitor cells (HSPCs) compartment [ 9 , 10 ], we have herein selected by fluorescence-activated cell sorting HSPCs defined as Lin- CD34+ CD38− expressing at least one of the leukemic stem cell markers (CD45RA or CD123; that is, Lin- CD34+ CD38− CD45RA+ CD123− or Lin- CD34+ CD38− CD45RA− CD123+, Supplementary Methods ), previously use...