美国贝勒医学院Margaret A. Goodell、英国康桑格研究所Mathijs A. Sanders等研究人员合作发现，DNMT3A突变克隆的扩增与保守的表观遗传丧失相关。 该研究于2020年7月15日在线发表于《细胞—干细胞》。

Title: Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion

Author: Ayala Tovy, Jaime M. Reyes, Michael C. Gundry, Lorenzo Brunetti, Henry Lee-Six, Mia Petljak, Hyun Jung Park, Anna G. Guzman, Carina Rosas, Aaron R. Jeffries, Emma Baple, Jonathan Mill, Andrew H. Crosby, Valerie Sency, Baozhong Xin, Heather E. Machado, Danielle Castillo, Jeffrey N. Weitzel, Wei Li, Michael R. Stratton, Peter J. Campbell, Heng Wang, Mathijs A. Sanders, Margaret A. Goodell

Issue&Volume: 2020-07-15

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 yearsbefore malignancies develop, but difficulties in comparing their impact before malignancywith wild-type cells have limited the understanding of their contributions to transformation.To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoidcell lines from a germline mosaic individual in whom these cells co-existed for nearly6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequencingrevealed similar mutational burdens and signatures in normal and mutant clones, whileepigenetic profiling uncovered the focal erosion of DNA methylation at oncogenic regulatoryregions in mutant clones. These regions overlapped with those sensitive to DNMT3Aloss after DNMT3A ablation in HSCs and in leukemia samples. These results suggestthat DNMT3A maintains a conserved DNA methylation pattern, the erosion of which providesa distinct competitive advantage to hematopoietic cells.

DOI: 10.1016/j.stem.2020.06.018

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30285-X