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Gaulin, C.;  Kelemen, K.;  Yi, C.A. Molecular Pathways in Clonal Hematopoiesis. Encyclopedia. Available online: https://encyclopedia.pub/entry/26055 (accessed on 16 July 2025).
Gaulin C,  Kelemen K,  Yi CA. Molecular Pathways in Clonal Hematopoiesis. Encyclopedia. Available at: https://encyclopedia.pub/entry/26055. Accessed July 16, 2025.
Gaulin, Charles, Katalin Kelemen, Cecilia Arana Yi. "Molecular Pathways in Clonal Hematopoiesis" Encyclopedia, https://encyclopedia.pub/entry/26055 (accessed July 16, 2025).
Gaulin, C.,  Kelemen, K., & Yi, C.A. (2022, August 10). Molecular Pathways in Clonal Hematopoiesis. In Encyclopedia. https://encyclopedia.pub/entry/26055
Gaulin, Charles, et al. "Molecular Pathways in Clonal Hematopoiesis." Encyclopedia. Web. 10 August, 2022.
Molecular Pathways in Clonal Hematopoiesis
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This entry is adapted from the peer-reviewed paper 10.3390/life12081135

Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of CH into clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) further describes this neoplastic myeloid precursor state and stratifies individuals at risk of developing clinically significant complications. The sequential acquisition of driver mutations, such as DNMT3A, TET2, and ASXL1, provide a selective advantage and lead to clonal expansion.

clonal hematopoiesis hematopoietic stem cell aging

1. Introduction

Hematopoietic stem cells (HSC) acquire somatic mutations with every mitotic division as we age [1][2][3]. While some mutations are passengers of minimal pathogenic consequence, others can promote cellular self-renewal, often at the cost of differentiation, and lead to clonal expansion [4]. The sequential acquisition of somatic driver mutations with oncogenic potential can shape mutant HSC clones into a neoplastic myeloid precursor state referred to broadly as clonal hematopoiesis (CH) [5][6][7][8]. Epigenetic changes, aging, inflammation, the microbiome, and the bone marrow microenvironment can all influence the landscape of CH [9][10]. In the absence of other hematologic ramifications, such as cytopenias or dysplastic hematopoiesis, this entity in stem cell biology was termed clonal hematopoiesis of indeterminate potential (CHIP) [11]. This perhaps universal marker of aging is associated with an increased risk of hematologic neoplasms, cardiovascular disease, all-cause mortality, and unexpectedly, a reduced risk of Alzheimer’s disease [12][13][14][15].

2. Epidemiology and Definitions

The prevalence of CH increases with age, although it varies based upon the defined variant allele frequency (VAF) detection threshold [16]. Using whole-exome sequencing and a threshold VAF > 2% in subjects unselected for hematologic phenotypes, initial large population studies estimated the prevalence of CH to be at least 5% in persons older than 60 years of age, while seldom occurring in younger persons [12][14][17]. Subsequent work using techniques allowing for the detection of CH mutations with a VAF of ≥0.01% found the prevalence of CH to be nearly ubiquitous in persons older than 50 years of age, although the clinical significance of clones with such a low VAF is uncertain [18][19].
The fifth edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours recently defined CHIP as the presence of a somatic mutation associated with myeloid neoplasia detected in the peripheral blood or bone marrow with a VAF ≥ 2% in the absence of definitive morphologic evidence of a hematologic disorder [20]. CHIP, when an associated cytopenia is present (hemoglobin < 13 g/dL in males or <12 g/dL in females for anemia, absolute neutrophil count < 1.8 × 109/L for leukopenia, and platelets < 150 × 109/L for thrombocytopenia), is defined as clonal cytopenia of undetermined significance (CCUS) [20]. Composed of a mixed group in which cytopenia is present with seemingly normal bone marrow morphology without identifiable clonality, idiopathic cytopenia of undetermined significance (ICUS) [11][21].

3. Acquisition of Mutations

The single cell origin hypothesis underlying cancer pathophysiology, with its hallmark stepwise acquisition of mutations conferring survival advantage, long predates the current understanding of the mechanisms driving HSC clonal evolution in CH [4][22]. Through the application of analogous principles, mutations predominantly in epigenetic regulators (DNMT3A, TET2, ASXL1, IDH1/2), splicing factors (SF3B1, SRSF2, U2AF1), DNA damage response (PPM1D, TP53), and signaling molecules (JAK2 V617F) affect HSC fitness and drive clonal expansion (Table 1) [4][9]. HSC clones with multiple drivers can then exhibit mutational cooperativity, further increasing their ability to thrive in the presence of selective pressures and establish clonal dominance [8]. Although still in early phases, the understanding of the evolutionary dynamics of CH has grown tremendously and has shed light on the early disease initiating steps of myeloid neoplasms.
Table 1. Common Driver Mutations in Clonal Hematopoiesis.
Mutation Class Prevalence Physiologic Function Oncogenic Mechanism
Epigenetic Regulators   Regulate gene expression through chromatin modification. Increased cellular self-renewal and proliferation, impaired differentiation.
DNMT3A 50%
TET2 15%
ASXL1 7%
IDH1/2 1%
Splicing Factors
SF3B1
SRSF2
U2AF1		 6% * Process mRNA through the removal of introns and retention of exons. Splicing alterations affecting cellular pathways conveying increased selective advantage.
DNA Damage Response
PPM1
DTP53		 5% * Maintain the integrity of the genome through repair mechanism engagement and regulation of apoptosis. Diminished response to genomic instability and increased cellular proliferation.
Signaling Molecules
JAK2 V617F		 3% Transmit extracellular signals through transmembrane receptors to target gene promoters. Cytokine signaling overactivation, proliferative and survival advantages in downstream hematopoietic precursors.

3.1. Epigenetic Regulators

By far the most common, loss-of-function mutations in DNA methyltransferase 3 alpha (DNMT3A) are found in approximately half of individuals with CH [12][14][23]. Playing an important role in HSC development, DNMT3A encodes for a de novo DNA methyltransferase enzyme responsible for establishing DNA methylation patterns which in turn impact gene expression [24]. Physiologically, epigenetic regulation of gene expression affects cell fate decisions and ultimately defines a cell’s final differentiated state [25]. While the exact mechanisms through which DNMT3A mutations contribute to CH are not fully elucidated, in murine models, a loss of DNMT3A leads to HSC division biased towards self-renewal, causing cellular expansion at the cost differentiation [26][27]. Analysis of clonal evolution in CH and myeloid neoplasms suggest that DNMT3A mutations are likely disease-initiating, may occur at an early age, and slow in growth in older age in the context of a competitive landscape [8][28][29]. Recent studies have explored the functional consequences of specific DNMT3A variants. Huang et al. evaluated 253 disease-associated DNMT3A variants using a CRISPR screen and found that in 74% of cases these variants led to a loss of DNMT3A function [30]. Approximately half of the DNMT3A variants exhibited protein instability which in turn was associated with clonal expansion and transformation to AML [30]. Hence, not all DNMT3A variants confer the same fitness effect. For instance, highly fit DNMT3A mutations at the R882 residue in CH and AML cells are associated with DNA hypomethylation and anthracycline resistance [31]. These findings suggest that DNMT3A mutations at the R882 residue, as well as other highly fit variants, confer a significant selective advantage, are less likely to be disease-initiating, and occur later with the acquisition of other mutated genes [8][23][32][33].
Mutations in ten-eleven translocation 2 (TET2) are the second most common in CH, affecting approximately 15% of individuals [4]. Physiologically, TET proteins are ultimately involved in DNA demethylation [34]. Loss-of-function TET2 mutations in CH are associated with DNA hypermethylation in a non-random and global manner; in AML, they occur in many loci in HSCs, suggesting that these mutations are initiating events and may also result in leukemic transformation [8][35][36][37]. Data by Fabre et al. demonstrated that TET2 mutations in CH can arise across multiple age groups, exhibit a consistent growth rate over time, and eventually overtake DNMT3A as the most prevalent in older age [29]. Loss of TET2 is associated with increased cellular self-renewal and impaired differentiation. However, this effect disproportionately impacts downstream myeloid progenitors rather than long-term HSCs [38]. While their physiologic function suggests an antagonistic effect, TET2 and DNMT3A mutations can co-occur and result in synergy, as their potentials vary [4][38]. Beyond these proliferative consequences, evidence also supports a link between TET2 mutations and immune function [39]. TET2 physiologically restrains inflammatory gene expression and, accordingly, TET2 loss-of-function mutations are associated with increased levels of proinflammatory cytokines [23][40][41][42]. Pre-clinical data suggests that vitamin C treatment mimics TET2 function in TET2 deficient cells and promotes cellular differentiation [43]. As a result of these findings, clinical studies exploring the impact of vitamin C supplementation in patients with hematologic neoplasms are ongoing (NCT03682029; NCT03418038).
Addition of sex combs such as 1 (ASXL1) mutations are present in approximately 7% of patients with CH [4][44]. ASXL1 loss-of-function, dominant negative, and gain-of-function mutations have been associated with altered polycomb repressive complex function leading to histone modification and dysregulated hematopoiesis [45][46][47][48]. ASXL1 mutations in murine models with CH activate the Akt/mTOR pathway leading to HSCs proliferation and dysfunction [49]. Although not well understood, ASXL1 mutations are likely early events in CH [48][49][50]. Interestingly, ASXL1 mutations have been associated with smoking, offering a potential mechanism for the increased risk of leukemia observed in smokers, and are also linked to pesticide exposure [9][51][52][53].
Mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) and its mitochondrial homolog isocitrate dehydrogenase 2 (IDH2) are far less common in CH than in AML, collectively representing <1% of mutations [4][54]. Physiologically, IDH1/2 play a key role in citrate metabolism, catalyzing the isocitrate to alpha-ketoglutarate (αKG) reaction in the Krebs cycle [55]. IDH1/2 mutations lead to the production of 2-hydroxyglutarate (2HG), which results in DNA hypermethylation, in part, through impaired αKG dependent TET2 catalytic function [54][55]. IDH1/2 and TET2 mutations are typically mutually exclusive, supporting the necessity of this downstream effect in leukemogenesis [47]. IDH1/2 mutations through these mechanisms ultimately impair cellular differentiation [55]. IDH1/2 mutations can be disease-initiating in CH, although they tend to occur later in life, and often in conjunction with DNMT3A mutations resulting in a synergistic selective advantage [8][28][56]. IDH1/2 mutations are early events in clonal evolution in MDS and AML, while they tend to appear later in MPNs, leading to leukemic transformation [57]. Reasons for their disproportionately higher implication in AML and relative absence in CH are unclear, although it could be related to differences in clonal fitness in the context of selective pressures and the surrounding microenvironment [47]. In a study incorporating subjects from the Women’s Health Initiative exploring the premalignant mutational landscape of AML, all subjects with IDH1/2 mutations eventually developed AML, highlighting the potential benefit of early intervention [58]. On a background of their efficacy in AML [59][60], phase 1 trials studying the mutant IDH1 inhibitor, ivosidenib, and the mutant IDH2 inhibitor, enasidenib, are both underway in patients with CCUS to determine their impact on hematologic parameters in this population (NCT05030441; NCT05102370).

3.2. Splicing Factors

Messenger RNA (mRNA) splicing plays a vital role in governing gene expression. Broadly, splicing renders pre-mRNA into its final form, through the catalysis of reactions leading to the removal of introns and retention of exons [61][62]. This complex process is orchestrated through interactions between pre-mRNA regulatory sequences, spliceosome machinery components, and specific splicing regulators [63]. The mature mRNA product is then translated into protein. Therefore, mutations resulting in alternative splicing can lead to protein products with variable functional consequences and contribute to oncogenesis through diverse pathways [64][65].
The most frequent splicing factor mutations in CH are in SF3B1, SRSF2, and U2AF1. Altogether, these make up approximately 6% of mutations observed in CH [4]. Recurrent splicing factor mutations were first observed in MDS but are also seen in AML, chronic lymphocytic leukemia, as well as other cancers [62][66][67][68]. Splicing factor mutations in CH tend to occur later in life, are associated with a rapid clonal growth rate, and a high risk of leukemic transformation [29][69]. Splicing factor and epigenetic regulator mutations often co-occur, suggesting mutational cooperativity in leukemogenesis [50][62][70]. Co-occurring IDH2 and SRSF2 mutations, for instance, result in more profound splicing alterations than either mutation alone [70]. An emerging candidate gene, ZBTB33, also links DNA methylation and mRNA splicing pathways to convey HSC selective advantage in CH and MDS, further strengthening the synergistic relationship between epigenetic regulation and post-transcriptional machinery [71]. Other oncogenic mechanisms include U2AF1 S34F related interleukin (IL) 8 upregulation, which affects bone marrow niche formation and is associated with a poor prognosis in AML [72][73]. SF3B1 and U2AF1 mutations can also cause overexpression of the highly active longer isoform of IL−1 receptor-associated kinase 4 (IRAK4), leading to activation of inflammatory signaling pathways and leukemogenesis [74][75]. A novel IRAK4 inhibitor, CA−4948, has shown promising clinical activity in individuals with MDS and AML, particularly those with splicing factor mutations, although has yet to be studied in CH [76].

3.3. DNA Damage Response

CH with mutated DNA damage response (DDR) related genes is of particular interest in the context of cytotoxic therapy [9][32][77]. Physiologically, the DDR maintains the integrity of the genome. When subjected to an insult, components of the DDR collectively sense DNA damage, engage repair mechanisms, and initiate various signaling pathways impacting associated cellular processes [78]. Thus, defects in these pathways can result in a diminished response to genomic instability and increased cellular proliferation.
While DDR related mutations in PPM1D and TP53 are less frequent, together making up approximately 5% of mutations in CH, clones with these mutations exhibit a selective advantage when exposed to radiotherapy, platinum agents, topoisomerase II inhibitors, and poly(adenosine diphosphate–ribose) polymerase inhibitors (PARPi) [4][9][79][80][81]. PPM1D physiologically interacts with the tumor suppressor protein, p53, ultimately leading to downregulation of p53-mediated apoptosis [82]. PPM1D mutations result in a gain-of-function truncated protein product, thereby downregulating apoptosis and promoting cellular survival [81]. Mutations leading to a loss of TP53 also provide a selective advantage through a diminished response to genomic instability [83][84]. Missense variants in the DNA binding domain of TP53 have been associated with particularly high HSC fitness [33][85]. Mutant p53 drives CH through interactions with EZH2 leading to epigenetic modulation [86]. Both PPM1D and TP53 mutations can be present at low frequencies prior to iatrogenic exposure and are enriched in therapy-related myeloid neoplasms (t-MNs) [14][81][83]. Hence, it is likely that pre-existing HSC clones harboring DDR mutations are preferentially selected when exposed to cytotoxic therapy. There has been a growing interest in better understanding the relationship between DDR mutated CH and the development of t-MNs to individualize the risk of chemotherapy [9]. In part due to their selective advantages, PPM1D and TP53 mutated t-MNs are associated with a reduced response to chemotherapy and are near-universally fatal [77][83][87][88]. PPM1D and EZH2 inhibitors may be a future approach to reduce the risk of t-MNs by preventing chemotherapy-induced selection of DDR mutated clones in those with CH [77][86].

3.4. Signaling Molecules

The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway physiologically transmits signals received from extracellular polypeptides through transmembrane receptors to target gene promoters in the nucleus, thereby influencing gene expression [89]. The JAK-STAT pathway is notably essential for the signaling of several cytokines [90].
The Janus kinase 2 (JAK2) V617F activating mutation is present in approximately 3% of individuals with CH [91][92]. Classically associated with MPNs, the JAK2 V617F mutation confers proliferative and survival advantages in downstream hematopoietic precursors, while reducing the self-renewal capacity of individual HSCs [93][94]. JAK2 mutations can be found early in life and may hence be disease initiating. However, these clones tend to have highly variable growth rates over time [28][29][95]. JAK2-mediated expansion of progenitors is thought to act as a reservoir in which other mutations can then be acquired, and through mutational cooperativity, lead to eventual leukemic transformation [4][96].

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