Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion.
DNMT3A
HSC
cell competition
clonal hematopoiesis
hematopoietic stem cells
mutation burden
mutation signature
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
23
10
2019
revised:
10
04
2020
accepted:
22
06
2020
pubmed:
17
7
2020
medline:
28
4
2021
entrez:
17
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32673568
pii: S1934-5909(20)30285-X
doi: 10.1016/j.stem.2020.06.018
pmc: PMC7494054
mid: NIHMS1608594
pii:
doi:
Substances chimiques
DNMT3A protein, human
0
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
DNA Methyltransferase 3A
EC 2.1.1.37
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
326-335.e4Subventions
Organisme : NIDDK NIH HHS
ID : R56 DK092883
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG036695
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242218
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183252
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK092883
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024574
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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