Clonal hematopoiesis of indeterminate potentialC (CHIP) describes the expansion of hematopoietic stem and progenitor cells bearing somatic mutations commonly associated with myeloid malignancies, in the absence of cytopenias or dysplastic features. This premalignant condition, an antecedent to myeloid malignancies such as MDS (Myelodysplastic Syndrome) and AML (Acute Myeloid Leukemia), was first formally defined in 2015 and is considered analogous to monoclonal gammopathy of undetermined significance (MGUS) within the myeloma spectrum. Both CHIP and MGUS are largely asymptomatic with an elevated risk for progression to overt malignancy [1]. The World Health Organization (WHO) defines CHIP as the presence of pathogenic mutations, typically in genes such as DNMT3A, TET2, ASXL1, JAK2, and SF3B1, at a variant allele fraction (VAF) ≥ 2%, in individuals without established hematologic disease or unexplained cytopenia [2]. These mutations lead to a proliferative advantage, usually through altered epigenetic regulation or resistance to inflammatory stress [3]. They are also associated with increased risk of hematologic neoplasms, cardiovascular disease, and all-cause mortality [4, 5].

CHIP is identified using Next-Generation Sequencing (NGS) platforms, including Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), and targeted panels. WES captures most pathogenic variants relevant for research, but targeted panels are more applicable to clinical diagnostics [6]. Additionally, with liquid biopsy platforms (cfDNA, ctDNA) often identifying CHIP mutations incidentally, the observed incidence, prevalence, and awareness of CHIP will continue to climb as these tests become widely used [7].

CHIP has recently been identified as a systemic modifier of inflammation and immune regulation. CHIP-associated mutations are linked to elevated levels of IL-6 and other proinflammatory cytokines, reflecting altered myeloid cell phenotypes that can potentiate local and systemic inflammatory responses [8, 9]. In experimental models, IL-6 signaling has been shown to propagate CHIP clonal expansion in the setting of bone marrow microenvironment (BME) changes associated with aging, obesity, and metabolic dysfunction [10, 11]. Similarly, CHIP has been mechanistically linked to a growing list of non-hematologic conditions including coronary artery disease, ischemic stroke, atherosclerosis, chronic liver disease, and autoimmune syndromes such as vasculitis and arthritis [12,13,14,15,16,17,18,19]. The proinflammatory macrophage-driven state induced by CHIP mutations, especially in DNMT3A and TET2, may amplify disease severity or affect therapeutic response [20,21,22].

This further highlights the evolving concept of CHIP as more than a pre-malignant lesion. The long latency period and high prevalence of CHIP in aging and at-risk populations for cancer make it a unique model of acquired somatic mosaicism with system-wide relevance [23]. Ongoing work aims to define how CHIP clones interact with local immune microenvironments, contribute to fibrogenesis, and shape neoplastic or pathogenic evolution across non-hematologic organ systems. This review will focus on the role of CHIP in inflammation-driven gastrointestinal conditions, particularly liver fibrosis, inflammatory bowel disease, and colorectal cancer.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) has led to increasing global health burden as it is projected to affect 27 million people in the United States by 2030 [24]. It develops following persistent hepatic injury, inflammation, and fibrogenesis [25]. Genetic contributors in hepatic lipid metabolism and lipotoxicity are increasingly recognized as central to MASLD progression, from lipid accumulation to severe scarring [26]. Mutations in the PNPLA gene are associated with hepatic steatosis, whereas ATG7 mutations increase the risk of hepatic cirrhosis and hepatocellular carcinoma (HCC) [27, 28]. Recent genomic analysis characterizes a phenomenon parallel to clonal hematopoiesis, where somatic mutations in metabolic genes like FOXO1 and CIDEB accumulate in chronic liver disease. These mutations render hepatocytes resistant to insulin, protecting them from lipotoxicity and driving clonal expansion. While this adaptation ensures cell survival in lipid laden hepatocytes, it worsens metabolic dysfunction in MASLD [29].

Recent studies have implicated CHIP as a novel contributor to the pathophysiology of chronic liver disease [30]. In a large population-based analysis, individuals with CHIP had nearly twice the odds of developing chronic liver disease (OR 2.01; variant allele frequency ≥ 10%; 95% CI, 1.46–2.79; p < 0.001) and increased risk of Metabolic dysfunction-Associated Steatohepatitis (MASH) (OR 1.87; 95% CI, 1.17–3.01; p = 0.008). These associations remained independent of smoking and alcohol use. Mechanistic studies using murine models demonstrated that mice transplanted with TET2-deficient hematopoietic cells developed hepatic lobular inflammation with lymphoid aggregates in the absence of steatosis. In contrast, inflammation was mitigated in TET2/NLRP3 double knockouts highlighting the importance of NLRP3-mediated signaling in TET2-driven hepatic injury. Kupffer cell–derived IL-6 was also identified as a key inflammatory mediator, echoing prior findings linking CHIP to NLRP3 activation in atherogenesis. These data suggest that TET2-mutant clones promote hepatic inflammation and fibrosis through paracrine cytokine signaling rather than direct steatotic injury [13].

CHIP's role in hepatocarcinogenesis has also been studied [31, 32]. In a study comparing patients with MASLD-HCC and those without HCC, CHIP was associated with a two-fold increased risk of malignancy (OR 2.01; 95% CI, 1.30–3.15; p = 0.002), independent of age, diabetes, and cirrhosis [31]. This association was more pronounced in males with attenuation after adjusting for age [31, 33]. TET2 mutations resulted in the highest relative risk, (OR 4.8; 95% CI, 1.6–17.0; p = 0.02) consistent with previous evidence [31]. In contrast, DNMT3A mutations showed no significant association with HCC and has been shown to be inversely correlated (OR 0.60; 95% CI, 0.27–1.22; p = 0.24) [31]. While JAK2 mutations were strongly linked to liver disease in earlier studies (OR 17.65; 95% CI, 4.32–72.15; p < 0.001), they were rarely identified in MASLD-HCC cases [13, 31]. Together, these findings emphasize the gene-specific roles of CHIP variants in hepatocarcinogenesis.

CHIP has also been implicated in immune complications following liver transplantation [34, 35]. In a retrospective analysis of patients with GVHD, DNMT3A mutations were observed in five of seven cases with available sequencing data, compared to just one of six non-GVHD patients (p = 0.04) [35]. In contrast, findings from a study with patients receiving HSCT with donor CH show that DNMT3A-related clonal hematopoiesis does not worsen transplant outcomes and is linked to lower relapse and better survival, particularly in recipients not given post-transplant cyclophosphamide (PTCy). The study reported no consistent increase in GVHD, and immune changes suggested a possible graft-versus-tumor effect. Donor CH clones could persist long-term without causing donor-cell leukemia when limited to DNMT3A or TET2 mutations [36, 37].

Available data are limited but suggest that DNMT3A-related clonal hematopoiesis may also be associated with a higher risk of GVHD after allogeneic HSCT. On a similar note, it has been proposed that a potentially enhanced graft-versus-leukemia effect in this setting could improve overall outcomes. Data from liver transplantation show a similar pattern, with DNMT3A-mutant clones enriched among patients who develop severe GVHD-like immune complications. These similarities likely reflect the overlapping immunologic landscapes of HSCT and solid-organ transplantation and underlying clonal hematopoiesis. In HSCT, donor DNMT3A-mutant clones engraft into a fully reconstituted immune system where post-transplant cyclophosphamide limits excessive alloreactivity, allowing DNMT3A-driven myeloid inflammation to potentiate anti-leukemic effects without triggering GVHD. In liver transplantation, however, DNMT3A-CH arises in the host bone marrow and interacts with a partly intact, immunosuppressed immune environment, where heightened IL-6/NLRP3 signaling from mutant myeloid cells amplifies dysregulated inflammation and predisposes to GVHD, cytopenias, and hemophagocytic syndromes. Taken together, these findings indicate that the impact of CHIP on post-transplant immunity is highly context-dependent, shaped by mutation type, cellular origin (donor vs recipient), immune reconstitution dynamics, and the specific immunosuppressive regimen.

Clonal hematopoiesis has long been associated with aging and an increased risk of hematologic malignancies, but its relationship with chronic inflammatory conditions such as inflammatory bowel disease (IBD) has only recently been explored in detail [38,39,40,41]. Emerging evidence suggests a bidirectional pathogenic axis between IBD and CHIP, wherein chronic intestinal inflammation may accelerate clonal hematopoietic expansion, while CHIP-related systemic inflammatory signaling may conversely predispose to the onset or worsening of IBD.

A large study by Selvan et al. found that age and treatment both had specific selective pressures on clonal populations. Individuals over the age of 45 years exhibit notably higher rates of myeloid (M-CHIP) in ulcerative colitis (UC) and lymphoid (L-CHIP) clones are seen in older IBD patients overall [42]. Younger Crohn’s disease (CD) patients were frequently seen to carry TET2 mutations, correlating with more severe inflammatory outcomes and heightened hematologic malignancy risk [42]. Steroid use was associated with increased CHIP (P = 0.05), while anti-TNF therapy was associated with decreased myeloid-CHIP (P = 0.03). Other studies have also shown increased risk of IBD in patients with CHIP, especially with mutations in JAK2, ASXL1 and DNMT3A, large CHIP clones and selective evolution of clonal population in this patient population [42].

Further investigations assessed whether chronic IBD-related inflammation accelerates malignant transformation. Earlier studies have reported higher risk of lymphoid malignancies within the first year of diagnosis, myeloid neoplasms (MN) overall and myelodysplastic syndrome (MDS) transplantation [43, 44]. With the widespread use of NGS for mutational profiling, it has been possible to look into CHIP and specific mutations to ascertain a biological mechanism for this increased risk. In an analysis done by Cumbo et al., 85% of the patients with IBD and associated hematologic malignancies were found to have CH mutations, most commonly DNMT3A. In several cases, individuals carried multiple driver mutations and showed dominant clonal populations with variant allele frequencies greater than 10%, suggesting that chronic inflammation may create a permissive environment that supports clonal expansion and increases the potential for malignant progression. This high prevalence may warrant frequent screening of these patients for associated myeloid malignancies [45].

Subsequent retrospective analyses have also revealed that there are early subtle hematologic disturbances in IBD patients preceding MN diagnoses, leading to MDS, challenging prior assumptions about cytopenias predominantly being microcytic and reactive [46,47,48,49]. Collectively, these findings suggest chronic intestinal inflammation in IBD reshapes hematopoietic clonal dynamics, selecting and expanding specific mutations leading to elevated risk of hematologic malignancy at younger ages, and increased severity of IBD.

Different clinical and preclinical studies support a strong association between CH and CRC [50, 51]. Early mechanistic evidence came from a mouse model of colitis-associated colon cancer driven by DNMT3A-mutated hematopoiesis; animals were seen to have a higher risk of development of adenocarcinoma, disease severity and tumor burden. These changes were accompanied by enhanced intratumoral angiogenesis that likely led to CRC progression, with response to the angiogenesis inhibitor axitinib, highlighting a potential therapeutic strategy for CH-driven CRC [52]. A large prospective study by Liu et al. demonstrated a 20% increase in risk of CRC in patients with CHIP (p 0.006), especially in females and individuals over the age of 60 years with TET2 and ATM gene mutations [53]. Another study by Desai et al. did not find an increase in the incidence of CRC in female patients with CHIP, where an increased risk of mortality was seen [54]. Findings from both these studies highlight the significant role of CHIP in disease and mortality risk, advocating for its role as a risk stratification tool.

CHIP is also found in various solid tumors, known as Tumor Infiltrating clonal hematopoiesis (TICH), which is emerging as an independent risk factor for disease recurrence and mortality [55,56,57,58]. CHIP mutations shape the tumor-immune interface by altering both the tumor microenvironment (TME) and systemic immune dynamics [59,60,61]. TET2 and DNMT3A mutations have been identified in immune cells within the TME and exert divergent effects depending on context by promoting or restraining tumor growth. In solid tumors treated with Immune Checkpoint Inhibitor therapy (ICI), CHIP may enhance anti-tumor immunity, whereas in the absence of ICI use, it may sustain the immunosuppressive function to promote tumorigenesis [20, 62, 63]. The role of CHIP in risk stratification extends beyond disease progression and therapeutic response to severity of adverse events, such as Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor T cell (CAR-T) therapy [64].

Conversely, results from a prospective analysis for CH in patients from the FIRE 3 trial, which investigated the use of FOLFIRI with cetuximab vs bevacizumab in metastatic CRC (mCRC) had contrasting findings. Although there was a significant presence of CH in 36% of patients with mCRC, most commonly involving DNMT3A, TET2, PPM1D, and ASXL1 mutations in older individuals with prior chemotherapy exposure, there was seen improved overall survival (OS), without any difference in progression-free survival (PFS). CH-positive patients had higher rates of grade 3 to 4 diarrhea and thromboembolic events [65]. These findings may be due to the CHIP-mediated immune environment for tumor control and potential enhancement of response to further lines of therapy, suggesting importance of cancer type and therapy in determining CHIP’s role in prognostication.

CHIP has also been associated with other GI cancers, like esophagoduodenal showing worse OS and pancreatic showing improved PFS in those treated with ICI compared to worse OS in those treated with conventional chemotherapy [51, 66]. Detection of CHIP may warrant increased surveillance for adverse events as seen in CRC. This highlights the need for further prospective studies to determine the prognostic significance of CH in specific tumor contexts. A deeper understanding of how specific CHIP mutations influence immune tone, whether proinflammatory or immunosuppressive, will be essential for developing risk stratification tools and targeted therapies for CRC and other solid tumors. (Fig. 1).

Associations of Clonal Hematopoiesis with GI pathology. Created with Biorender.com

Outside of primary GI pathology, CHIP is also seen in conditions presenting with GI symptoms. VEXAS syndrome is a severe adult-onset inflammatory disease caused by somatic mutations in UBA1 in myeloid precursors. Loss of functional UBA1 disrupts the ubiquitin-activating enzyme E1 pathway resulting in impaired protein degradation, activation of the unfolded protein response, and chronic innate immune signaling [67, 68]. Clinically, VEXAS presents with systemic inflammation, cytopenias, chondritis, vasculitis, and skin findings. Gastrointestinal symptoms occur in some patients and usually manifest as abdominal pain, diarrhea, and bleeding related to vasculitis or granulomatous bowel involvement. TET2 and DNMT3A mutations are frequently co-detected in affected individuals [69]. Conventional immunosuppressive therapy may be ineffective in these patients because mutation-driven, cell-intrinsic activation of the myeloid clone sustains inflammation despite broad dampening of immune cells. Thus, allogeneic hematopoietic stem cell transplantation is currently being explored as a potential curative approach [68].

These syndromes reflect the capacity of CHIP-related mutations to induce chronic inflammation in the gastrointestinal tract independent of inherited immunodeficiencies. Recognizing these presentations is critical for early diagnosis and consideration of mutation-directed therapies in patients with atypical or treatment-resistant GI inflammation.