Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms

Yun Soo Hong, Sergiu Pasca, Wen Shi, Daniela Puiu, Nicole J. Lake, Monkol Lek, Meng Ru, Megan L. Grove, Anna Prizment, Corinne E. Joshu, Elizabeth A. Platz, Eliseo Guallar, Dan E. Arking () and Lukasz P. Gondek ()
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Yun Soo Hong: Johns Hopkins University School of Medicine
Sergiu Pasca: Johns Hopkins University School of Medicine
Wen Shi: Johns Hopkins University School of Medicine
Daniela Puiu: Johns Hopkins University
Nicole J. Lake: Yale School of Medicine
Monkol Lek: Yale School of Medicine
Meng Ru: Johns Hopkins Bloomberg School of Public Health
Megan L. Grove: The University of Texas Health Science Center at Houston
Anna Prizment: University of Minnesota Medical School
Corinne E. Joshu: Johns Hopkins University School of Medicine
Elizabeth A. Platz: Johns Hopkins University School of Medicine
Eliseo Guallar: New York University
Dan E. Arking: Johns Hopkins University School of Medicine
Lukasz P. Gondek: Johns Hopkins University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Clonal hematopoiesis of indeterminate potential is the primary pathogenic risk factor for myeloid neoplasms, while heteroplasmy (mutations in a subset of cellular mitochondrial DNA) is another marker of clonal expansion associated with hematological malignancies. We explore how these two markers relate and influence myeloid neoplasms incidence, and their role in risk stratification. We find that heteroplasmy is more common in individuals with clonal hematopoiesis of indeterminate potential, particularly those with higher variant allele fractions, multiple mutations, or spliceosome machinery mutations. Individuals with both markers have a higher risk of myeloid neoplasms than those with either alone. Furthermore, heteroplasmic variants with higher predicted deleteriousness increase the risk of myeloid neoplasms. Incorporating heteroplasmy in an existing risk score model for individuals with clonal hematopoiesis of indeterminate potential significantly improves sensitivity and better identifies high-risk groups. This suggests heteroplasmy as a clonal expansion marker and potentially as a biomarker for myeloid neoplasms development.

Date: 2024
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DOI: 10.1038/s41467-024-54443-3

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