Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation
Open accessAbstract
Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A. We have recently shown that Dnmt3a is essential for hematopoietic stem cell differentiation. Here, we investigated the effect of loss of Dnmt3a on hematopoietic transformation by forcing the normally quiescent hematopoietic stem cells to divide in vivo. Mice transplanted with Dnmt3a-null bone marrow in the absence of wildtype support cells succumbed to bone marrow failure (median survival, 328 days) characteristic of myelodysplastic syndromes with symptoms including anemia, neutropenia, bone marrow hypercellularity, and splenomegaly with myeloid infiltration. Two out of 25 mice developed myeloid leukemia with >20%blasts in the blood and bone marrow. Four out of 25 primary mice succumbed to myeloproliferative disorders, some of which progressed to secondary leukemia after long latency. Exome sequencing identified cooperating c-Kit mutations found only in the leukemic samples. Ectopic introduction of c-Kit variants into a Dnmt3a-deficient background produced acute leukemia with a short latency (median survival, 67 days). Our data highlight crucial roles of Dnmt3a in normal and malignant hematopoiesis and suggest that a major role for this enzyme is to facilitate developmental progression of progenitor cells at multiple decision checkpoints.
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Dnmt3a heterozygous hematopoietic stem cells produce only modest phenotypes in mice.
“However, we and others have shown that Dnmt3a HET HSCs produce only modest phenotypes in mice (25,26), likely because these variants provide very minor fitness advantages to HSCs (2) that require the extended lifespan of humans to manifest measureable phenotypes.”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [26]
Stem cells from mice with loss-of-function mutations in TET2 or DNMT3A are able to serially replate in colony forming assays over many generations, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells.
“Stem cells from these mice are able to serially replate in colony forming assays over many generations, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells 54,55.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [55]
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- Authors
- Celik, H., Mallaney, C., Kothari, A., Ostrander, E. L., Eultgen, E., Martens, A., Miller, C. A., Hundal, J., Klco, J. M., & Challen, G. A.
- Affiliations
- Division of Oncology, Department of Internal Medicine,
- Department of Pediatrics,
- The Genome Institute, and
- Department of Pathology & Immunology,
- Washington University in St. Louis (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2015-01-22
- Volume
- 125
- Issue
- 4
- Pages
- 619-628
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC4304107
- OpenAlex
- W2015603297
- Cited by
- 95
- References
- 42
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 4 · 2022: 12 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 6 · 2017: 9 · 2016: 18 · 2015: 11
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Children's Discovery Institute
- Edward Mallinckrodt, Jr. Foundation
- Alvin J. Siteman Cancer Center (CA91842)
- National Institutes of Health (CA91842)
- National Heart, Lung, and Blood Institute (K08HL116605, T32HL007088)
- National Cancer Institute (CA91842, T32CA113275, P30CA091842)
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK084259, DK084259, R00DK084259)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD043010)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- DNMT3A, KIT mutations, myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, hematopoietic stem cells, hematopoietic differentiation, epigenetic machinery, bone marrow failure, secondary leukemia, hematopoiesis, cooperating mutations
- MeSH terms
- DNA Methyltransferase 3A, Animals, Blast Crisis, Bone Marrow, Cell Differentiation, Cell Line, Cell Transformation, Neoplastic, DNA (Cytosine-5-)-Methyltransferases, Hematopoiesis, Hematopoietic Stem Cells, Mutation, Leukemia, Myeloid, Acute, Mice, Knockout, Proto-Oncogene Proteins c-kit, Mice
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