Mitochondrial heteroplasmy is a risk factor for the development of chronic lymphocytic leukemia

Why tiny cell batteries matter for leukemia risk

Chronic lymphocytic leukemia (CLL) is a common blood cancer of older adults, yet doctors still struggle to predict who will develop it. This study explores an unexpected warning sign hidden inside our cells’ “power plants” – the mitochondria. By looking at subtle genetic changes in mitochondrial DNA across hundreds of thousands of people, the researchers show that these tiny alterations can flag individuals at higher risk for CLL, even when other known warning signs are absent.

Clues beyond known blood cell mutations

Until now, one of the strongest predictors of future blood cancer was a condition called clonal hematopoiesis, where a small fraction of blood-forming cells acquires mutations and begins to expand. When this involves genes linked to lymphoid cancers, it is called lymphoid clonal hematopoiesis of indeterminate potential, or L-CHIP. People with L-CHIP are more likely to develop CLL, but most CLL patients never show these mutations beforehand, leaving a major gap in early detection. The authors set out to find other, more widely present molecular footprints that might forecast CLL risk.

Reading the mitochondrial mutation signature

The team analyzed genetic data from over 419,000 participants in the UK Biobank, excluding anyone who already had CLL or unexplained high lymphocyte counts. They focused on “heteroplasmy,” a state where not all copies of mitochondrial DNA inside a cell are identical. Because mitochondria have less robust DNA repair than the nucleus, their DNA often accumulates mutations with age, smoking, and other stresses. The researchers used whole-genome sequencing to catalog mitochondrial variants and calculated a score reflecting how damaging each person’s mix of mutations was, summing these into an overall burden measure.

Higher-risk mitochondrial patterns and future leukemia

Individuals with any detectable mitochondrial heteroplasmy were about 1.5 times more likely to develop CLL over nearly 14 years of follow-up than those without it, even after accounting for age, sex, smoking, and prior cancer. More strikingly, people whose mitochondrial variants were predicted to be especially harmful had roughly a fourfold higher risk. When both the sheer number of mitochondrial changes and their predicted impact were examined together, it was the harmfulness, not just the count, that best tracked with CLL risk. These findings held up when the team repeated the analysis in a separate U.S. cohort from the All of Us Research Program, strengthening confidence that the signal is real and not a fluke.

How mitochondrial changes connect to known blood precancers

The study also examined how mitochondrial changes interact with L-CHIP. As expected for a marker of aging blood clones, heteroplasmy was more common in people with L-CHIP and in those whose L-CHIP clones were larger or carried particularly risky gene mutations. Among all participants, having L-CHIP alone strongly increased CLL risk, and having both L-CHIP and mitochondrial heteroplasmy raised it even further. Yet most people who eventually developed CLL did not have detectable L-CHIP at baseline, whereas mitochondrial heteroplasmy remained a meaningful predictor on its own in this larger, L-CHIP–negative group. This suggests that mitochondrial DNA changes capture a broader slice of individuals quietly moving toward leukemia.

What this means for patients and prevention

To a non-specialist, the central message is that the state of our cells’ power plants may help reveal who is drifting toward chronic lymphocytic leukemia long before symptoms appear. While current tools based on nuclear DNA mutations miss most future CLL cases, mitochondrial heteroplasmy—especially when the mutations are predicted to damage mitochondrial function—identifies additional at-risk individuals. The work does not yet prove that these mitochondrial changes cause leukemia, but it strongly supports the idea that they contribute to how pre-cancerous blood cell clones grow and survive. In the future, combining mitochondrial metrics with existing genetic and blood-based markers could improve early risk stratification and guide closer monitoring or preventive research in people most likely to develop CLL.

Citation: Pasca, S., Hong, Y.S., Shi, W. et al. Mitochondrial heteroplasmy is a risk factor for the development of chronic lymphocytic leukemia. Nat Commun 17, 2898 (2026). https://doi.org/10.1038/s41467-026-69861-8

Keywords: chronic lymphocytic leukemia, mitochondrial DNA, heteroplasmy, clonal hematopoiesis, cancer risk prediction