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

Chronic lymphocytic leukemia (CLL) can arise from lymphoid clonal hematopoiesis of indeterminate potential (L-CHIP), but many individuals who develop CLL lack detectable L-CHIP prior to diagnosis. To identify additional predictors of CLL risk, we analyze mitochondrial heteroplasmy in 419,154 individuals from the UK Biobank (UKB). Heteroplasmy is associated with a 1.5-fold increased risk of developing CLL, and this risk rises to 4-fold when accounting for deleterious heteroplasmic variants. These findings are confirmed in an independent cohort, the All of Us Research Program (AoU). Notably, the associations remain significant even in the absence of L-CHIP, highlighting heteroplasmy's potential utility as an independent biomarker. Moreover, heteroplasmy is enriched in individuals with high-risk L-CHIP genotypes and large clonal burden, suggesting a potential biological role in malignant transformation. Here, we show that mitochondrial heteroplasmy, especially functionally deleterious variants, identifies individuals at increased risk of CLL who would otherwise go undetected by L-CHIP-based assessments.