Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion.
Cell Stem Cell
; 27(2): 326-335.e4, 2020 08 06.
Article
in En
| MEDLINE
| ID: mdl-32673568
ABSTRACT
DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in clonal hematopoiesis (CH). Somatic DNMT3A mutations arise in hematopoietic stem cells (HSCs) many years before malignancies develop, but difficulties in comparing their impact before malignancy with wild-type cells have limited the understanding of their contributions to transformation. To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoid cell lines from a germline mosaic individual in whom these cells co-existed for nearly 6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequencing revealed similar mutational burdens and signatures in normal and mutant clones, while epigenetic profiling uncovered the focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSCs and in leukemia samples. These results suggest that DNMT3A maintains a conserved DNA methylation pattern, the erosion of which provides a distinct competitive advantage to hematopoietic cells.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA (Cytosine-5-)-Methyltransferases
/
Hematopoiesis
Type of study:
Risk_factors_studies
Language:
En
Journal:
Cell Stem Cell
Year:
2020
Document type:
Article
Affiliation country:
Estados Unidos