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Cited by 219Acute Myeloid Leukemia ResearchEpigenetics and DNA MethylationChromatin Remodeling and Cancer

CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression

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Spencer, David H., Russler-Germain, David A., Ketkar, Shamika, Helton, Nichole M., Lamprecht, Tamara L., Fulton, Robert S., Fronick, Catrina C., O’Laughlin, Michelle +11 more·2017·Cell
DOI 10.1016/j.cell.2017.01.021PMC PMC5328582
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Abstract

DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A R882H, has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A R882 mutations. Non-leukemic hematopoietic cells with DNMT3A R882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3A R882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3A R882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.

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  • Focal changes in DNA methylation in DNMT3A-mutant samples may have important biological consequences.

    “However, it has been shown that focal changes in DNA methylation in DNMT3A-mutant samples may have important biological consequences (18,37).”

    From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [18]

    The Results report focal methylation changes in DNMT3A-mutant cells, and the Discussion suggests that DNMT3A-dependent methylation may have tumor-suppressor activity. But the Discussion also says the downstream cellular and molecular consequences remain unclear, so this paper does not establish that the focal changes have important biological consequences. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Focal methylation alterations appear physiologically relevant.

    “yet focal methylation alterations appear physiologically relevant (17,18,37,41).”

    From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [18]

    The Introduction says that focal methylation changes occur in cancer and that, in some cases, altered methylation is associated with expression of genes related to cancer pathogenesis. That supports possible physiological relevance, but the Discussion says the downstream consequences of the changes studied in AML remain unclear and reports few reproducible transcriptional effects. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Analysis of DNA methylation and gene expression patterns in mouse and human systems has yet to identify a unifying molecular mechanism to explain the increased fitness of Dnmt3a-mutant hematopoietic stem cells.

    “However, analysis of DNA methylation and gene expression patterns in mouse (15,17) and human (17,18) systems have yet to identify a unifying molecular mechanism to explain the increased fitness of these mutant HSCs.”

    From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [18]

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Authors
Spencer, D. H., Russler-Germain, D. A., Ketkar, S., Helton, N. M., Lamprecht, T. L., Fulton, R. S., Fronick, C. C., O’Laughlin, M., Heath, S. E., Shinawi, M., Westervelt, P., Payton, J. E., Wartman, L. D., Welch, J. S., Wilson, R. K., Walter, M. J., Link, D. C., DiPersio, J. F., & Ley, T. J.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Ley, Timothy J.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2017-02
Volume
168
Issue
5
Pages
801-816.e13
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2017.01.021
PMC
PMC5328582
OpenAlex
W2587989857
Cited by
219
References
49
Citations by year
2026: 11 · 2025: 17 · 2024: 21 · 2023: 19 · 2022: 20 · 2021: 32 · 2020: 35 · 2019: 27 · 2018: 20 · 2017: 17
FWCI
20.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • ASH Scholar Award (K08CA190815)
  • NIH (P01CA101937, R35CA197561)
  • National Cancer Institute Cancer Center (P30CA91842)
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 › Chromatin Remodeling and Cancer
Keywords
DNMT3A, acute myeloid leukemia, CpG island hypermethylation, DNA methylation, leukemogenesis, DNA hypomethylation, hematopoietic stem cells, leukemia progression, gene silencing, dominant negative effect
MeSH terms
DNA Methyltransferase 3A, Bone Marrow Cells, DNA (Cytosine-5-)-Methyltransferases, Humans, Mutation, Leukemia, Myeloid, Acute, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Epigenesis, Genetic

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