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.
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.


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.
Mossner
Maximilian
M
Department of Hematology, Oncology and Transfusion Medicine, Charité, University Hospital Benjamin Franklin, Berlin, Germany. max.mossner@charite.de
Hopfer
Olaf
O
Nowak
Daniel
D
Baldus
Claudia D
CD
Neumann
Uwe
U
Kmetsch
Anke
A
Benlasfer
Ouidad
O
John
Thilo
T
Perka
Carsten
C
Thiel
Eckhard
E
Hofmann
Wolf-Karsten
WK
D018952:Antigens, CD34; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008938:Mitosis; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D018952:Antigens, CD34; D004273:DNA, Neoplasm; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors