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Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in Lin - CD34 + CD38 - HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients.
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“CHIP mutations originate in multipotent HSCs, the clonal progeny is predominantly concentrated within the myeloid compartment, specifically affecting monocytes and granulocytes, with a significantly lower mutational burden observed in lymphoid cells [29].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [29]
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Metadata
- Authors
- Arends, C. M., Galan-Sousa, J., Hoyer, K., Chan, W., Jäger, M., Yoshida, K., Seemann, R., Noerenberg, D., Waldhueter, N., Fleischer-Notter, H., Christen, F., Schmitt, C. A., Dörken, B., Pelzer, U., Sinn, M., Zemojtel, T., Ogawa, S., Märdian, S., Schreiber, A., Kunitz, A., Krüger, U., Bullinger, L., Mylonas, E., Frick, M., & Damm, F.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Kyoto University (JP)
- Max Delbrück Center (DE)
- ORCID
- Venue
- Leukemia
- Published
- 2018-03-01
- Volume
- 32
- Issue
- 9
- Pages
- 1908-1919
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2789900003
- Cited by
- 194
- References
- 50
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 25 · 2023: 26 · 2022: 31 · 2021: 30 · 2020: 20 · 2019: 27 · 2018: 6
- FWCI
- 14.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- clonal hematopoiesis of indeterminate potential, clonal hematopoiesis, variant allele frequency, DNMT3A, hematopoietic stem cells, chemotherapy, hematologic cancer, red blood cell transfusion
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alleles, Cell Differentiation, DNA Mutational Analysis, Female, Gene Frequency, Hematopoiesis, Hematopoietic Stem Cells, Humans, Male, Middle Aged, Mutation, Biomarkers, Immunophenotyping, Polymorphism, Single Nucleotide, Clonal Evolution
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