Mitochondrial DNA Mutations May Help Identify Individuals at Risk of CLL

New research suggests that mutations in mitochondrial DNA, long considered a byproduct of cellular aging, may play a more active role in the development of chronic lymphocytic leukemia (CLL) than previously understood.¹

The large population-based study, published in Nature Communications, identified mitochondrial heteroplasmy as an independent risk factor for CLL, offering a potential new biomarker for identifying individuals at increased risk of the disease. While further functional studies will be required to clarify causality, the findings suggest that mitochondrial heteroplasmy may serve as a complementary biomarker for identifying individuals at elevated risk of CLL who might otherwise go undetected through traditional genetic screening approaches.

The most common form of leukemia in adults, CLL often arises from clonal expansions of abnormal lymphocytes over time. In recent years, researchers have focused on lymphoid clonal hematopoiesis of indeterminate potential (L-CHIP), a condition in which blood stem cells acquire mutations linked to lymphoid malignancies, as a precursor state associated with increased leukemia risk. However, many patients who eventually develop CLL do not have detectable L-CHIP prior to diagnosis, suggesting that additional biological drivers may be involved.

Researchers of this new study analyzed mitochondrial heteroplasmy in more than 419,000 participants enrolled in the UK Biobank (UKB), one of the largest population-based genomic datasets available. Heteroplasmy refers to the presence of both mutated and wild-type mitochondrial DNA (mtDNA) within a single cell or individual.²

The analysis revealed a significant association between mitochondrial heteroplasmy and future development of CLL. Individuals with 1 or more heteroplasmic mutations had a 1.5-fold higher risk of developing CLL compared with those without detectable heteroplasmy (HR, 1.5; 95% CI, 1.3-1.8; P < .0001), even after adjusting for age, sex, smoking status, and prior cancer history.¹

Notably, the risk increased substantially when researchers accounted for the functional impact of specific variants. Using a modified mitochondrial local constraint score to assess the likely deleterious effects of each mutation, the group found that patients harboring more harmful heteroplasmic variants faced more than a 4-fold increase in CLL risk (HR, 4.0; 95% CI, 2.7-5.9; P < .0001).

These results were validated in an independent cohort drawn from the US-based All of Us Research Program, where individuals with heteroplasmic mutations were approximately twice as likely to develop CLL during follow-up (HR, 2.0; 95% CI, 1.3-3.1; P = .001).

Beyond its association with incident disease, mitochondrial heteroplasmy also appeared to intersect with known genetic risk factors. Individuals with L-CHIP were more likely to harbor heteroplasmic mutations, particularly those with large clonal expansions or high-risk genetic variants. Notably, heteroplasmy was significantly more common among carriers of high-risk L-CHIP genotypes compared with individuals without L-CHIP.

The combination of both risk factors proved especially concerning. Participants with concurrent L-CHIP and mitochondrial heteroplasmy demonstrated more than a 7-fold higher risk of developing CLL relative to individuals lacking either marker.

The researchers also observed notable findings in the subset of patients without detectable L-CHIP. In this group, which represents the majority of patients who ultimately developed CLL, mitochondrial heteroplasmy remained independently associated with increased leukemia risk (Hr, 1.5; 95% CI, 1.2-1.8; P < .0001). The presence of deleterious mtDNA mutations was linked to incident disease even after adjusting for heteroplasmy count, suggesting that these mutations may contribute directly to leukemogenesis rather than simply reflecting age-related clonal expansion.

The researchers acknowledged several limitations of their study, writing, “First, L-CHIP has a low prevalence in the general population and a heterogeneous distribution across genotypes leading to a relatively low power to detect true associations. Second, mosaic CAs were not evaluated in the current study, which may be major drivers of CLL. Nonetheless, mosaic CAs responsible for lymphoid malignancies were shown to account for less than 1% of individuals in the UKB, making it unlikely for mosaic CAs to completely explain the effect of heteroplasmy.”

The group also highlighted that the patients included in UKB belong to 1 ancestry, resulting in volunteer bias.

References

1. Pasca S, Hong YS, Shi W, et al. Mitochondrial heteroplasmy is a risk factor for the development of chronic lymphocytic leukemia. Nat Commun. Published online February 18, 2026. doi:10.1038/s41467-026-69861-8

2. Heteroplasmy. ScienceDirect. Accessed February 22, 2026. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/heteroplasmy