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Cited by 35Acute Myeloid Leukemia ResearchEpigenetics and DNA MethylationDNA Repair Mechanisms

Remethylation of Dnmt3a −/− hematopoietic cells is associated with partial correction of gene dysregulation and reduced myeloid skewing

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Ketkar, Shamika, Verdoni, Angela M., Smith, Amanda M., Bangert, Celia V., Leight, Elizabeth R., Chen, David Y., Brune, Meryl K., Helton, Nichole M. +10 more·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1918611117PMC PMC7022185
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Abstract

Mutations in the DNA methyltransferase 3A ( DNMT3A ) gene are the most common cause of age-related clonal hematopoiesis (ARCH) in older individuals, and are among the most common initiating events for acute myeloid leukemia (AML). The most frequent DNMT3A mutation in AML patients (R882H) encodes a dominant-negative protein that reduces methyltransferase activity by ∼80% in cells with heterozygous mutations, causing a focal, canonical DNA hypomethylation phenotype; this phenotype is partially recapitulated in murine Dnmt3a −/− bone marrow cells. To determine whether the hypomethylation phenotype of Dnmt3a −/− hematopoietic cells is reversible, we developed an inducible transgene to restore expression of DNMT3A in transplanted bone marrow cells from Dnmt3a −/− mice. Partial remethylation was detected within 1 wk, but near-complete remethylation required 6 mo. Remethylation was accurate, dynamic, and highly ordered, suggesting that differentially methylated regions have unique properties that may be relevant for their functions. Importantly, 22 wk of DNMT3A addback partially corrected dysregulated gene expression, and mitigated the expansion of myeloid cells. These data show that restoring DNMT3A expression can alter the epigenetic “state” created by loss of Dnmt3a activity; this genetic proof-of-concept experiment suggests that this approach could be relevant for patients with ARCH or AML caused by loss-of-function DNMT3A mutations.

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Authors
Ketkar, S., Verdoni, A. M., Smith, A. M., Bangert, C. V., Leight, E. R., Chen, D. Y., Brune, M. K., Helton, N. M., Hoock, M., George, D. R., Fronick, C., Fulton, R. S., Ramakrishnan, S. M., Chang, G. S., Petti, A. A., Spencer, D. H., Miller, C. A., & Ley, T. J.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Ley, Timothy J.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-01-29
Volume
117
Issue
6
Pages
3123-3134
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1918611117
PMC
PMC7022185
OpenAlex
W3004078246
Cited by
35
References
9
Citations by year
2026: 3 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 9 · 2021: 9 · 2020: 4
FWCI
3.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
Funders
  • NIH (CA101937, CA197561, 211782)
  • Foundation for Barnes-Jewish Hospital (615762)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
DNMT3A, age-related clonal hematopoiesis, acute myeloid leukemia, DNA hypomethylation, differentially methylated regions, gene expression dysregulation, myeloid skewing, bone marrow transplantation, epigenetic reprogramming, hematopoietic cells
MeSH terms
DNA Methyltransferase 3A, Animals, Bone Marrow Cells, DNA (Cytosine-5-)-Methyltransferases, Hematopoiesis, Humans, Mice, Transgenic, Mutation, Gene Expression, Bone Marrow Transplantation, DNA Methylation, Mice

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