AI Article Synopsis

  • - DNMT3A is the most frequently mutated gene associated with clonal hematopoiesis (CH), and these mutations occur in blood stem cells long before any related cancer develops.
  • - By studying an individual with both normal and mutant DNMT3A cells over decades, researchers found that while mutant cells predominated in the blood, both cell types had similar mutation rates.
  • - The study revealed that DNMT3A mutations lead to a loss of DNA methylation in critical regulatory regions, giving mutant cells an edge over normal cells in the blood system.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494054PMC
http://dx.doi.org/10.1016/j.stem.2020.06.018DOI Listing

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