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

Abstract

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 agerelated 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.

Contribution of epigenetic mechanisms to variation in cancer risk among tissues

“…It was further suggested that this elemental property has its effect by controlling the number of intrinsic mutations that each tissue accumulates and in this way influences cancer risk. Previous experiments have already demonstrated that normal cells accumulate aberrant methylation, perhaps as a function of aging (11,12). Our studies, however, indicate that the amount of aberrant methylation that takes place in normal tissues is closely correlated with lifetime cancer risk, raising the possibility that this epigenetic change may also contribute to tumor susceptibility.…”

“…This pattern appears to involve a similar set of sites in all tumors but varies quantitatively between different cell types (11). Furthermore, as opposed to some methylation events that take place after tumor formation, the abnormal CpG island modification profile can already be observed to some degree in normal tissues where it probably develops as a function of aging (11,12), upstream to tumor transformation.…”

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes

“…(tubulin tyrosine ligase-like family, member 8) gene is differentially methylated in diseases such as myelodysplastic syndrome (57), and OR2T6 shows copy number gains in many cancers, including HNSCC (http://ow.ly/RniAf).…”

Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors

“…More recent work has even identified these blocks in medulloblastomas without obvious genetic drivers, underscoring the importance of this type of epigenetic change in cancer, [8]. Large-scale hypomethylated blocks have also been associated with Epstein-Barr virus-induced B-cell immortalization [9], neuronally expressed genes [10], epigenetic changes prior to morphological transformation [11] age-related drift in the pathogenesis of MDS and AML [12].…”