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The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the  NUP98-HOXD13  ( NHD13 ) mouse and the  RUNX1  mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in  NHD13  MDS, and 331 (9.6%) genes hypermethylated in  RUNX1  MDS. Thirty-two percent of genes in common between the two models (2/3  NHD13  mice and 2/3  RUNX1  mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.

Age-related epigenetic drift in the pathogenesis of MDS and AML