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Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes
Open accessAbstract
Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.
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“While the standard diagnostic threshold is often set at 2%, high-sensitivity sequencing can detect small clones at levels as low as 0.5%”
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 [2]
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“reaching approximately 39% in individuals older than 60 years when utilizing high-sensitivity sequencing (Variant Allele Fraction (VAF) greater than 0.5%) [2,3]”
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 [2]
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“Most large-population-based studies define CHIP using a VAF threshold of ≥2%, reflecting the lower limit of reliable detection in standard whole-exome sequencing pipelines [2,32].”
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 [2]
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“Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition affecting over 10–20% of individuals older than 70 years”
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“in healthy elderly individuals, DNA mutations in specific loci are associated with the establishment of clonal hematopoiesis”
From Aging of hematopoietic stem cells (2018) · cites this paper as [52]
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“A gain of novel bivalent domains is observed in ageing cells 65,66 (Figure 2),”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [66]
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“In ageing cells, a gain of novel bivalent domains is observed, mostly due to gains of repressive H3K27me3 marks on regions that were marked by the active histone modification H3K4me3 in young cells 65,66 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [66]
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“Bivalent domains show the lowest DNA methylation in normal cells 66 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [66]
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Metadata
- Authors
- Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., & Ebert, B. L.
- Affiliations
- Brigham and Women's Hospital (US)
- University of California San Diego (US)
- Cleveland Clinic (US)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2015-07-02
- Volume
- 126
- Issue
- 1
- Pages
- 9-16
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC4624443
- OpenAlex
- W1985823023
- Cited by
- 1,971
- References
- 87
- Citations by year
- 2026: 133 · 2025: 156 · 2024: 176 · 2023: 229 · 2022: 222 · 2021: 221 · 2020: 202 · 2019: 182 · 2018: 181 · 2017: 149 · 2016: 99 · 2015: 16
- FWCI
- 115.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Edward P. Evans Foundation
- National Heart, Lung, and Blood Institute (T32HL066987)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK091360)
- 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 › Hematological disorders and diagnostics
- Keywords
- clonal hematopoiesis of indeterminate potential, myelodysplastic syndrome, somatic mutations, clonal expansion, aging, hematopoietic stem cells, myeloid neoplasms, diagnostic criteria, monoclonal gammopathy of undetermined significance, monoclonal B-cell lymphocytosis, cytopenia, dysplastic hematopoiesis
- MeSH terms
- Diagnosis, Differential, Hematopoiesis, Humans, Monoclonal Gammopathy of Undetermined Significance, Mutation, Myelodysplastic Syndromes, Precancerous Conditions, Hematologic Neoplasms, Clonal Evolution
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