Prognostic implications of mitochondrial inheritance in myelodysplastic syndromes after stem-cell transplantation

摘要 骨髓增生异常综合征(MDS)是一组克隆性造血干细胞疾病， 以无效的造血为特征，并有发展为急性髓系白血病的趋势 病人们。目前治疗MDS的唯一方法是异基因造血干细胞移植。 (Hct)。然而，由于疾病复发和移植相关的并发症，HCT后的死亡率很高。 目前常用的红细胞压积MDS预后模型仅考虑了非遗传因素，因此不能 准确预测HCT后的结局。因此，迫切需要新的预测标记来识别 最有可能从HCT中受益的患者。线粒体在造血细胞中起着至关重要的作用 动态平衡和分化。线粒体DNA(MtDNA)的遗传和表观遗传改变可损害 线粒体功能及其在MDS中的病理生理作用。这一职业发展奖将 为董博士提供培训和研究经验，支持她成为一名医生的长期职业目标 综合分子流行病学的独立研究员，专注于应用最先进的技术 组学技术和创新的基于人群的流行病学方法，以减轻艾滋病患者的负担 血液病。虽然董博士在遗传学和流行病学方面接受了全面的培训，但她 需要进一步培训与红细胞压积相关的结局和表观遗传学的方法学。她已经组建了一支 指导团队由主要导师、基因组科学主任劳尔·乌鲁蒂亚博士和 精准医学中心，基因组学、表观基因组学和精准医学领域的知名领导者；以及两个 共同导师：Wael Saber博士，急慢性白血病工作教授兼科学主任 CIBMTR专门研究HCT和MDS的委员会；教授和癌症中心核心Paul Auer博士 具有统计和生物信息学专业知识的主任。利用现有的全基因组测序 来自CIBMTR《MDS基因组和表观遗传学研究》的数据，董博士将专注于线粒体 解决上述研究空白的基因组：1)确定线粒体基因组图谱 与异基因造血干细胞移植后MDS结局相关；2)量化mtDNA拷贝数并评估其相关性 与HCT后MDS结局相关；以及3)确定与MDS结局相关的mtDNA甲基化情况 在HCT之后。这些发现将提高我们对MDS病因的理解，并提供更多的分子 HCT后MDS结局的预测指标有助于制定个性化的风险预测和针对性 治疗。

ABSTRACT Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders, characterized by ineffective hematopoiesis and a tendency to progress to acute myeloid leukemia in 30% of the patients. Currently the only curative therapy for MDS is allogeneic hematopoietic stem-cell transplantation (HCT). However, the mortality after HCT is high due to relapsed disease and transplant-related complications. The commonly used MDS prognostic models for HCT only consider non-genetic factors, thus could not accurately predict the outcomes after HCT. Novel predictive markers are therefore critically needed to identify patients who are most likely to benefit from HCT. Mitochondria play a critical role in hematopoietic cell homeostasis and differentiation. Genetic and epigenetic alterations in mitochondrial DNA (mtDNA) can impair mitochondrial functions and play a pathophysiological role in MDS. This Career Development Award will provide training and research experience to Dr. Dong to support her long-term career goal of becoming an independent investigator in integrative molecular epidemiology, with a focus on applying state-of-the-art omics technologies and innovative population-based epidemiologic methods to reduce the burden of hematologic diseases. While Dr. Dong has had comprehensive training in genetics and epidemiology, she requires further training in methodologies of HCT-related outcomes and epigenetics. She has assembled a mentoring team comprised of a primary mentor, Dr. Raul Urrutia, Director in the Genomic Sciences and Precision Medicine Center and renowned leader in genomics, epigenomics and precise medicine; and two co-mentors: Dr. Wael Saber, Professor and Scientific Director in the Acute and Chronic Leukemia Working Committees in the CIBMTR specializing in HCT and MDS; Dr. Paul Auer, Professor and Cancer Center Core Director with expertise in statistics and bioinformatics. Leveraging the existing whole genome sequencing data from the “MDS Genomics and Epigenetics Study” in the CIBMTR, Dr. Dong will focus on mitochondrial genome to address the research gaps mentioned above: 1) determine mitochondrial genomic landscape associated with MDS outcomes after allo-HCT; 2) quantify mtDNA copy number and evaluate its associations with MDS outcomes after HCT; and 3) identify mtDNA methylation profiles associated with MDS outcomes after HCT. The findings will improve our understanding of MDS etiology and provide additional molecular predictors of MDS outcomes after HCT to help developing individualized risk prediction and targeted treatments.