Mitochondrial DNA (mtDNA) variants in patients with myelodysplastic neoplasms (MDS) are shown to be prognostic of outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). However, the prognostic impact of donor mtDNA variants is unknown. Here, we performed whole-genome sequencing on 494 donors who were matched to MDS patients enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR). We evaluated the impact of donor mtDNA variants on recipients’ transplantation outcomes, including overall survival, relapse, relapse-free survival, and transplant-related mortality. The optimism-adjusted bootstrap method was employed to evaluate the prognostic performance of models that include donor mtDNA variants alone and combined with MDS- and HCT-related clinical factors. In the entire donor cohort, we identified 1,825 mtDNA variants, including 67 potential pathogenic variants. Genetic variants on MT-CYB and MT-ND5 genes were identified as independent predictors of posttransplant outcomes. Integration of donor mtDNA variants into the models based on the International Prognostic Scoring System-Revised (IPSS-R) could capture more prognostic information for MDS patients. Sensitivity analysis in 397 unrelated donors obtained similar results. More importantly, we found that incorporating donor mtDNA variants with donor age and the degree of HLA-matching could help to identify “suboptimal” younger HLA-well-matched unrelated donors and “optimal” older HLA-partially/mismatched unrelated donors. Our study shows that mtDNA variants in donors, including those from unrelated donors, hold prognostic value for MDS patients undergoing allo-HCT and augment the prognostic stratification of current scoring systems. These findings present an opportunity to refine donor selection strategies and improve posttransplant outcomes for MDS patients.

中文翻译：

---

供体线粒体基因组变异对干细胞移植后骨髓增生异常肿瘤的预后影响


骨髓增生异常肿瘤 （MDS） 患者的线粒体 DNA （mtDNA） 变异被证明是同种异体造血细胞移植 （allo-HCT） 后预后的结果。然而，供体 mtDNA 变异的预后影响尚不清楚。在这里，我们对 494 名供体进行了全基因组测序，这些供体与国际血液和骨髓移植研究中心 （CIBMTR） 注册的 MDS 患者相匹配。我们评估了供体 mtDNA 变异对受者移植结局的影响，包括总生存期、复发率、无复发生存期和移植相关死亡率。采用乐观调整的 bootstrap 方法评估单独包括供体 mtDNA 变异并结合 MDS 和 HCT 相关临床因素的模型的预后表现。在整个供体队列中，我们鉴定了 1,825 个 mtDNA 变异，包括 67 个潜在的致病性变异。MT-CYB 和 MT-ND5 基因的遗传变异被确定为移植后结局的独立预测因子。将供体 mtDNA 变异整合到基于国际预后评分系统修订版 （IPSS-R） 的模型中可以为 MDS 患者捕获更多预后信息。对 397 名无关供体的敏感性分析获得了类似的结果。更重要的是，我们发现将供体 mtDNA 变异与供体年龄和 HLA 匹配程度相结合有助于识别“次优”年轻 HLA 匹配良好的无关供体和“最佳”老年 HLA 部分/不匹配的无关供体。我们的研究表明，供体中的 mtDNA 变异，包括来自无关供体的 mtDNA 变异，对接受同种异体 HCT 的 MDS 患者具有预后价值，并增强了当前评分系统的预后分层。 这些发现为改进供体选择策略和改善 MDS 患者的移植后预后提供了机会。