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Cited by 53Acute Lymphoblastic Leukemia researchAcute Myeloid Leukemia ResearchT-cell and Retrovirus Studies

Dnmt3a regulates T-cell development and suppresses T-ALL transformation

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Kramer, A C, Kothari, A, Wilson, W C, Celik, H, Nikitas, J, Mallaney, C, Ostrander, E L, Eultgen, E +7 more·2017·Leukemia
DOI 10.1038/leu.2017.89PMC PMC5636646
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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises ~15% and 25% of pediatric and adult ALL cases, respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus, which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.

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  • Reduced Nr4a1 in Dnmt3a-mutant hematopoietic progenitors leads to suppression of apoptosis.

    “leading to suppression of apoptosis (Kramer et al., 2017).”

    From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Kramer et al., 2017

    The Discussion says Dnmt3aKO-derived DN2 thymic progenitors have reduced apoptosis partially due to Nr4a1 downregulation. The claim omits “partially” and extends this finding from DN2 thymic progenitors to Dnmt3a-mutant hematopoietic progenitors generally. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Nr4a1 is reduced in Dnmt3a-mutant hematopoietic progenitors.

    “Nr4a1 has been reported to be reduced in Dnmt3a-mutant hematopoietic progenitors”

    From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Kramer et al., 2017

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Authors
Kramer, A. C., Kothari, A., Wilson, W. C., Celik, H., Nikitas, J., Mallaney, C., Ostrander, E. L., Eultgen, E., Martens, A., Valentine, M. C., Young, A. L., Druley, T. E., Figueroa, M. E., Zhang, B., & Challen, G. A.
Affiliations
  • Washington University in St. Louis (US)
  • University of Michigan (US)
Corresponding author
Challen, G A
ORCID
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
2017-03-21
Volume
31
Issue
11
Pages
2479-2490
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
DOI
10.1038/leu.2017.89
PMC
PMC5636646
OpenAlex
W2599031674
Cited by
53
References
3
Citations by year
2026: 5 · 2025: 7 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 13 · 2020: 7 · 2019: 4 · 2018: 8 · 2017: 1
FWCI
5.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Leukemia (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Alvin J. Siteman Cancer Center
  • Georgia Clinical and Translational Science Alliance
  • National Institutes of Health (UL1TR000448, UL1TR002345)
  • National Heart, Lung, and Blood Institute (F32HL080880, T32HL007088)
  • National Institute on Drug Abuse (R25DA027995)
  • National Cancer Institute (T32CA113275, P30CA091842)
  • National Institute of Allergy and Infectious Diseases (T32AI007172)
  • National Institute of Diabetes and Digestive and Kidney Diseases (F31DK111058)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
Keywords
DNMT3A, T-cell acute lymphoblastic leukemia, T cell development, DNA methylation, tumor suppressor, conditional knockout mouse model, hematopoietic cells, leukemic transformation
MeSH terms
DNA Methyltransferase 3A, Animals, Cell Line, DNA (Cytosine-5-)-Methyltransferases, Humans, Mice, Inbred C57BL, T-Lymphocytes, Apoptosis, Mice, Knockout, DNA Methylation, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

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