Mitochondrial Genetic Variation as a Novel Predictor of Graft-versus-Host Disease After Stem-Cell Transplantation in Myelodysplastic Neoplasms

Variation in the mitochondrial genome carries prognostic information about graft-versus-host disease (GvHD) that current clinical risk scores do not capture. These findings, published in the Journal of Hematology & Oncology, stem from authors at the Medical College of Wisconsin in Milwaukee, with collaborators at the Center for International Blood and Marrow Transplant Research (CIBMTR), the National Cancer Institute, and King Faisal Specialist Hospital and Research Centre in Riyadh. The analysis shows that adding recipient mitochondrial DNA (mtDNA) genes to the CIBMTR acute GvHD Risk Index (GRI) improved discrimination for severe acute disease by 11%.

GvHD remains a leading cause of morbidity and non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT), the only curative option in myelodysplastic neoplasms (MDS), and non-HLA genetics may contribute to risk. Building on earlier work linking mtDNA variation to allo-HCT outcomes, the authors performed whole-genome sequencing on pretransplant samples from 494 MDS donor-recipient pairs transplanted between 2014 and 2018, identifying 2,666 recipient and 1,825 donor variants. Gene-based associations across 16 mtDNA genes or regions were tested with SKAT-O inside cause-specific Cox models, censoring patients who died without prior GvHD and adjusting for recipient age, donor age, donor type, and GvHD prophylaxis. Outcomes were acute GvHD grades II-IV (aGvHD24), grades III-IV (aGvHD34), and chronic GvHD (cGvHD), with replication in an independent cohort of 295 MDS recipients using targeted deep sequencing.

Gene-based recipient signals emerged for the D-Loop, MT-ND1, MT-ND2, MT-ND3, and MT-tRNA with aGvHD24, and for the D-Loop, MT-ND1, MT-CYB, MT-CO1, MT-CO2, and MT-tRNA with cGvHD. In validation, recipient MT-ND2 replicated for aGvHD34 (p = 1.1 × 10⁻³) and MT-CYB for cGvHD (p = 3.6 × 10⁻³); MT-CO2, only nominal in discovery (p = 0.004), reached significance (p = 3.2 × 10⁻³). In validation, recipient genes improved aGvHD34 prediction (AUC 0.722; p = 0.009) but not aGvHD24 (p = 0.083). Overall, the authors suggest that mitochondrial genotype is fixed, obtainable from the same pretransplant sample already drawn from both donor and recipient, and appears to carry GvHD risk information that clinical scoring misses, making it a practical candidate for refining donor selection and prophylaxis intensity.

Reference

Arsang-Jang S, Zhang T, Rafati M, et al. Mitochondrial genetic variation as a novel predictor of graft-versus-host disease after stem-cell transplantation in myelodysplastic neoplasms. J Hematol Oncol. 2026;19:79 https:doi.org/10.1186/s13045-026-01846-y