Detection of differential mitotic cell age in bone marrow CD34(+) cells from patients with myelodysplastic syndrome and acute leukemia by analysis of an epigenetic molecular clock DNA signature

Abstract

Objective: Recently, the "epigenetic molecular clock hypothesis" linked increasing DNA methylation in a distinct CpG island in the cardiac-specific homeobox gene (CSX) gene to relative mitotic cell age. To determine mitotic cell age in hematopoietic cells of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients, we assessed differential CSX methylation patterns in these diseases vs age-adjusted healthy controls.

Materials and methods: We performed bisulfite pyrosequencing to analyze CSX methylation in CD34(+) and bone marrow (BM) cells from 53 MDS, 62 AML, 77 ALL patients, and 37 controls.

Results: Analysis of MDS CD34(+) and BM cells revealed significantly increasing methylation of CSX in controls < MDS low-risk < MDS high-risk < AML. Furthermore, increased differences of CSX methylation between the CD34(+) vs the unselected BM compartment were detected in matched MDS low-risk but not high-risk and AML samples. ALL samples displayed highly elevated CSX methylation levels as compared to controls.

Conclusions: Assessment of mitotic cell age by CSX methylation analysis could reveal novel insights into the distinct progression of hematologic diseases.