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Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies
Open accessAbstract
Clonal hematopoiesis (CH) broadly describes the expansion of a clonal population of blood cells with one or more somatic mutations. Individuals with CH are at greater risk for hematological malignancies, cardiovascular disease, and increased mortality from non-hematological cancers. Understanding the causes of CH and how these mutant cells interact with cells of other tissues will provide critical insights into preleukemic development, stem cell biology, host-immune interactions, and cancer evolution. Here we discuss the clinical manifestations of CH, mechanisms contributing to its development, the role of CH in clonal evolution toward leukemia, and the contribution of CH to non-hematological disease states.
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“clonal hematopoiesis-associated mutations alter the behavior of hematopoietic stem cells (HSCs); some also confer a fitness advantage, leading to clonal expansion [27,28].”
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 [28]
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“…CH-associated genes span a diverse set of cellular functions and processes, including epigenetic regulation, transcription, and RNA splicing, 7,8 the resulting effect of a CH driver mutation is enhanced cellular fi tness, leading to a selective advantage for the clone and subsequent clonal…”
InfluentialGlasdegib in newly diagnosed acute myeloid leukemia
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“A fraction of these mutations can confer the cells a competitive advantage, resulting in the clone expansion of the hematopoietic stem and progenitor cells(HSPCs) or clonal hematopoiesis, that is expanded somatic cell clone derived from a single mutant progenitor cell[1, 5].”
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Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
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“…of hematologic malignancies, cardiovascular diseases (CVD), all-cause mortality, and more recently, solid tumors and infectious diseases (2, 7, 14–19 Although intensive research in recent years has led to the identification of some 60 CH driver genes (1, 12, 13, 21), we have only a…”
Landscape of TET2 Mutations: From Hematological Malignancies to Solid Tumors
Hawking, Z. L., & Allan, J. M. (2025) · Cancer Medicine · doi:10.1002/cam4.70792 · Cited by 12
MLLT10 in benign and malignant hematopoiesis
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“However, it remains to be investigated whether TET2 variants that belong to different categories are unevenly distributed in myeloid neoplasia, solid tumors and tumor‐infiltrating lymphocytes, and whether they would have different effects on atherogenesis (Bowman et al., 2018).”
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“It will be important to explore further the impact of these proteins and the chromatin landscape on the GAS6-AXL-STAT5 AML progression axis.(16,17) A previous study also examined the effects of PI3K/AKT/mTOR inhibitors on a FLT3-ITD AML cell line compared with a cell line harboring point mutations within the TKD2 doma…”
BackgroundTreating accelerated and blast phase myeloproliferative neoplasms: progress and challenges
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Micro‐environment alterations through time leading to myeloid malignancies
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“The strongest associations were observed for mutations in TP53 and for mutations in spliceosome genes ( SRSF2 [splicing factor, arginine/serine-rich 2 gene], U2AF1 [splicing factor U2AF 35 kDa subunit]) and SF3B1 [splicing factor 3B subunit 1]) (Bolton et al., 2020; Bowman et al., 2018).”
Epigenetic Dysregulation of Myeloproliferative Neoplasms
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BackgroundInduced pluripotent stem cell models of myeloid malignancies and clonal evolution
Reilly, A., & Doulatov, S. R. (2021) · Stem Cell Research · doi:10.1016/j.scr.2021.102195 · Cited by 9
“Broadly speaking, the goal of iPSC differentiation is to recapitulate the later definitive wave of hematopoiesis that specifies HSCs.”
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TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cellsPreprint
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“A broad spectrum of human TET2 mutations is observed in clonal hematopoiesis (CH), a condition that may progress to myelodysplastic and myeloproliferative neoplasms, and various forms of leukemia ( 5 – 7 ).”
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Clonal selection parallels between normal and cancer tissues
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RNA binding protein‐directed control of leukemic stem cell evolution and function
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“9,106,107 MDS is also an age ‐ related stem cell ‐ driven hematopoietic premalignancy with approximately 30% of patients progressing to highly refractory secondary AML.”
BackgroundClonal hematopoiesis, cardiovascular disease and cancer treatment-induced cardiotoxicity
Zhang, N., Tian, X., Sun, D.-K., Tse, G., Xie, B., Zhao, Z., & Liu, T. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.02.007 · Cited by 7
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“Further genetic drift can be promoted by coexisting intrinsic DNA repair defects, loss of immunogenic tumor surveillance, remodeling of the BM microenvironment and other niche-factors associated with ageing [17] (Figure 1).”
BackgroundXie, Q., Tang, Z., Liang, X., Shi, Z., Yao, Y., Huang, X., Zhu, S., Wu, M., Li, J., Zhao, W., et al. (2022) · Hematology · doi:10.1080/16078454.2022.2122281 · Cited by 8
“over, TP53 mutation is associated with clonal hematopoiesis (CH) and can promote leukemogenesis and transformation [17].”
BackgroundChicken or Egg: Is Clonal Hematopoiesis Primarily Caused by Genetic or Epigenetic Aberrations?
Cypris, O., Božić, T., & Wagner, W. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00785 · Cited by 8
“…and overexpression of specific transcripts of DNMT3A has complementary effects on the DNA methylation pattern, gene expression, and differentiation of hematopoietic progenitor cells—thus, alternative splicing of DNMT3A has characteristic epigenetic and functional effects (Božić et al., 2018).”
Clonality in haematopoietic stem cell ageing
Terradas-Terradas, M., Robertson, N., Chandra, T., & Kirschner, K. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111279 · Cited by 8
“(HSCs) while ASXL1 - a member of the polycomb repressive complex - is involved in chromatin remodelling and affects hematopoietic repopulating capacity and expansion of the haematopoietic stem cell compartment (Bowman et al., 2018; Challen et al., 2011; Fuster et al., 2017; Jeong et al., 2018; Ko et al., 2011; Li et a…”
Impact of clonal hematopoiesis on cardiovascular outcomes in cancer patients of the UK Biobank
Sun, M., Busque, L., Sandoval, J., Perreault, L. L., Barhdadi, A., Cyr, M., Tardif, J., & Dubé, M. (2025) · ESMO Open · doi:10.1016/j.esmoop.2025.105539 · Cited by 7
Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia
Shukla, M., Abdul‐Hay, M., & Choi, J. (2024) · Biomedicines · doi:10.3390/biomedicines12081768 · Cited by 6
“…transformation involve the accumulation of genetic aberrations, including somatic mutations or epigenetic changes in immature cells of myeloid origin and/or abnormal changes in chromosomes, leading to the activation of pathways that promote the aberrant clonal proliferation of affected cells [2].”
BackgroundSong, J., Niu, Z., Yang, K., Wang, L., Huang, Y., Rao, Q., Liu, H., Hao, X., & Li, Y.-M. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117424 · Cited by 6
Watt, S. M., & Roubelakis, M. G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020671 · Cited by 7
Min, Y. K., Lee, Y. K., Nam, S.-H., Kim, J. K., Park, K., & Kim, J. (2020) · Clinical Chemistry · doi:10.1093/clinchem/hvaa088 · Cited by 7
The Field of Cell Competition Comes of Age: Semantics and Technological Synergy
Maheden, K., Zhang, V. W., & Shakiba, N. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.891569 · Cited by 7
“…in hematopoietic stem cell competition, where clones of stem cells with speci fi c receptor expression levels or mutations predispose them to surviving in that stem cell state over the long term ( Figure 1C ) (Cosgun et al., 2014; Shin et al., 2014; Bowman et al., 2018; Jaiswal and Ebert, 2019).”
BackgroundYu, C., Sheng, Y., Yu, F., Ni, H., Qiu, A., Huang, Y., & Qian, Z. (2023) · Journal of Clinical Investigation · doi:10.1172/jci163911 · Cited by 7
“While LSCs in AML possess enhanced self-renewal capacity, Foxm1 overexpression may contribute to MLL-AF9–induced leukemogenesis by enhancing HSC self-renewal and quiescence.”
BackgroundInfluentialTHERAPY-RELATED MYELOID NEOPLASMS: PREDISPOSITION AND CLONAL EVOLUTION
Fabiani, E., Falconi, G., Cristiano, A., Hajrullaj, H., Falconi, G., Leone, G. G. M., & Voso, M. T. (2023) · Mediterranean Journal of Hematology and Infectious Diseases · doi:10.4084/mjhid.2023.064 · Cited by 6
“49 Genovese et al. showed that subjects with CHIP have a higher risk of progression to hematological malignancies than subjects without mutated clones, which appears proportional to the VAF of mutated genes.”
BackgroundConcise Review: Exploiting Unique Biological Features of Leukemia Stem Cells for Therapeutic Benefit
Zhang, H., & Li, S. (2019) · Stem Cells Translational Medicine · doi:10.1002/sctm.18-0247 · Cited by 6
SWI/SNF subunit expression heterogeneity in human aplastic anemia stem/progenitors
Sinha, S., Chatterjee, S. S., Biswas, M., Nag, A., Banerjee, D., De, R., & Sengupta, A. (2018) · Experimental Hematology · doi:10.1016/j.exphem.2018.03.005 · Cited by 6
Pine, A. B., Chokr, N., Stahl, M. F., Steensma, D. P., Sekeres, M. A., Litzow, M. R., Luger, S. M., Stone, R. M., Greenberg, P. L., Bejar, R. L., et al. (2020) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2020.1723013 · Cited by 6
Clonal hematopoiesis in sickle cell diseasePreprint
Liggett, L. A., Cato, L. D., Weinstock, J. S., Zhang, Y., Nouraie, M. S., Gladwin, M. T., Garrett, M. E., Ashley‐Koch, A. E., Telen, M. J., Custer, B., et al. (2021) · medRxiv · doi:10.1101/2021.06.12.21258772 · Cited by 6
Impact of radiotherapy site, modality, and dose on subsequent clonal hematopoiesis
Goglia, A. G., Mustion, G., Modlin, L. A., Levine, R. L., Bolton, K. L., & Braunstein, L. Z. (2025) · Blood Advances · doi:10.1182/bloodadvances.2025016376 · Cited by 6
Modeling the evolutionary dynamics of clonal hematopoiesis
Marzban, S., Stiehl, T., Xie, Z., Andersen, M., Snyder, J. A., Gudmand‐Hoeyer, J., Ottesen, J. T., Père, N. V. M., Werner, B., Huang, W., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02504-2 · Cited by 7
Immunological consequences of chemotherapy: implications for cancer immunotherapy
Bishara, G. G., Umphred-Wilson, K., Abrams, S. I., Ohm, J. E., & Olejniczak, S. H. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-014099 · Cited by 5
CLL dedifferentiation to clonally related myeloid cells
Dong, Q., Xiu, Y., Bossler, A., Syrbu, S., Wang, H., Xue, W., Zhao, J., Li, Q., Jin, M., Wang, L., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002726 · Cited by 5
IRE1α maintains HSC stemness under ER-stress
Scheller, M., & Müller‐Tidow, C. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0295-4 · Cited by 5
Cellular and Molecular State of Myeloid Leukemia Stem Cells
Xie, X., Feng, M., Wang, Q., Wang, J., Yin, R. L., Li, Y., & Zhang, H. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-7342-8_2 · Cited by 5
Pediatric aplastic anemia treatment patterns and responses; power in the numbers
Fox, L. C., & Ritchie, D. S. (2019) · Haematologica · doi:10.3324/haematol.2019.225870 · Cited by 5
Lap, C. J. G., Nassereddine, S., Liu, M., Nava, V. E., & Aggarwal, A. (2021) · Case Reports in Hematology · doi:10.1155/2021/2348977 · Cited by 5
“More importantly, the R1261H missense mutation in the epigenetic modifier TET2 is a recurrent abnormality identified in (therapy-related) myeloid malignancies and is considered a driver of clonal hematopoiesis [21].”
BackgroundWhen should transplant physicians think about familial blood cancers?
Trottier, A. M., Bannon, S. A., Bashir, Q., Carraway, H. E., Hofmann, I., & Godley, L. A. (2019) · Advances in Cell and Gene Therapy · doi:10.1002/acg2.68 · Cited by 5
Quantifying mutations in healthy blood
Curtis, C. N. (2020) · Science · doi:10.1126/science.aba9891 · Cited by 6
A View of Myeloid Transformation through the Hallmarks of Cancer
Fernández-Maestre, I., Cai, S. F., & Levine, R. L. (2024) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-24-0009 · Cited by 4
Hosuru, R. V., Yang, J., Zhou, Y.-F., Gin, A. L., Hayal, T. B., Hong, S. G., Dunbar, C. E., & Wu, C. (2024) · British Journal of Haematology · doi:10.1111/bjh.19889 · Cited by 4
“22 Murine limit dilution transplantation and in vitro culture models have been used to investigate haematopoiesis at a clonal level, but have limitations based on species differences and non-physiologic conditions.”
Exploring the intricate cross-talk between clonal expansion and the bone marrow niche
Ngo, S. D., Papazoglou, D., Encabo, H. H., & Bonnet, D. A. (2024) · Frontiers in Hematology · doi:10.3389/frhem.2024.1334807 · Cited by 4
Metadata
- Authors
- Bowman, R. L., Busque, L., & Levine, R. L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Hôpital Maisonneuve-Rosemont (CA)
- Corresponding author
- Levine, Ross L.
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 22
- Issue
- 2
- Pages
- 157-170
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC5804896
- OpenAlex
- W2786854070
- Cited by
- 448
- References
- 112
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 37 · 2023: 56 · 2022: 54 · 2021: 69 · 2020: 67 · 2019: 71 · 2018: 25
- FWCI
- 9.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Cancer Institute (P30 CA008748)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- clonal hematopoiesis, somatic mutations, hematologic malignancies, leukemia, clonal evolution, hematopoietic stem cells, cardiovascular disease, tumor evolution
- MeSH terms
- Hematopoiesis, Humans, Mutation, Stochastic Processes, Hematologic Neoplasms, Epigenesis, Genetic, Clonal Evolution
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