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Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia
Open accessAbstract
In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.
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“Recent studies in patients with AML have confirmed the functional importance and clinical significance of preleukemic stem cell populations as the cellular origin of leukemia-initiating cells in human disease27, 48.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [48]
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“DNMT3A is also recurrently mutated in blood diseases such as acute myeloid leukemia (AML; ref. 9) and myelodysplastic syndromes (MDS; ref. 10) where it functions as an initiating mutation (11).”
From Txnip Enhances Fitness of Dnmt3a -Mutant Hematopoietic Stem Cells via p21 (2022) · cites this paper as [11]
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“In later studies, DNA sequencing of HSCs from AML patients in remission revealed that stem cells with only a single driver mutation were often present, suggesting that pre-malignant clonal hematopoiesis was a generalizable finding in AML 23–25.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [24]
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Metadata
- Authors
- Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., Kennedy, J. A., Schimmer, A. D., Schuh, A. C., Yee, K. W., McLeod, J. L., Doedens, M., Medeiros, J. J. F., Marke, R., Kim, H. J., Lee, K., McPherson, J. D., Hudson, T. J., Pan-Leukemia Gene Panel Consortium, T. H., Brown, A. M. K., Yousif, F., Trinh, Q. M., Stein, L. D., Minden, M. D., Wang, J. C. Y., & Dick, J. E.
- Affiliations
- University Health Network (CA)
- Chonnam National University (KR)
- Ontario Institute for Cancer Research (CA)
- Corresponding author
- Dick, John E.
- ORCID
- Venue
- Nature
- Published
- 2014-02-12
- Volume
- 506
- Issue
- 7488
- Pages
- 328-333
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4991939
- OpenAlex
- W2076031927
- Cited by
- 1,443
- References
- 53
- Citations by year
- 2026: 50 · 2025: 48 · 2024: 75 · 2023: 95 · 2022: 94 · 2021: 110 · 2020: 136 · 2019: 131 · 2018: 139 · 2017: 160 · 2016: 153 · 2015: 159 · 2014: 88
- FWCI
- 132.63
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-04-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Hospital for Sick Children
- Canadian Institutes of Health Research (105367_1)
- National Cancer Institute (R21CA152613)
- 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 › Retinoids in leukemia and cellular processes
- Keywords
- acute myeloid leukemia, DNMT3A mutation, NPM1 mutation, clonal evolution, treatment resistance, relapse, clonal expansion, chemotherapy remission, tumor heterogeneity, xenografts, mutation order, hematopoiesis
- MeSH terms
- DNA Methyltransferase 3A, Nucleophosmin, Animals, Cell Differentiation, Cell Division, Clone Cells, DNA (Cytosine-5-)-Methyltransferases, Female, Hematopoiesis, Hematopoietic Stem Cells, Humans, Isocitrate Dehydrogenase, Mutation, Neoplasm Transplantation, Nuclear Proteins, Remission Induction, T-Lymphocytes, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Cell Lineage, Mice, Heterografts
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