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

干细胞移植后骨髓增生异常综合征线粒体遗传的预后意义

• 批准号: 10662946
• 负责人: Jing Dong
• 金额: $ 15.66万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662946
• 关键词: Acute; Acute Myelocytic Leukemia; Acute leukemia; Address; Affect; Allogenic; Bioinformatics; Biological Markers; Bone Marrow; Bone marrow failure; Cancer Center; Candidate Disease Gene; Cells; Clinical; Clinical Data; Clonal Hematopoietic Stem Cell; Cytogenetics; DNA Methylation; DNA Sequence Alteration; Data; Decision Making; Disease; Disease-Free Survival; Dysmyelopoietic Syndromes; Enrollment; Epidemiologic Methods; Epidemiology; Epigenetic Process; Etiology; Exhibits; Future; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genomics; Goals; HLA Antigens; Haplogroup; Hematological Disease; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Impairment; Ineffective Hematopoiesis; Inferior; Iron; K-Series Research Career Programs; Knowledge; Medical; Medicine; Mentors; Methodology; Methylation; Mitochondria; Mitochondrial DNA; Mitochondrial Inheritance; Modification; Molecular; Molecular Epidemiology; Morbidity - disease rate; Morphology; Mutation; Nuclear; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Play; Ploidies; Prognostic Marker; Recommendation; Recurrent disease; Relapse; Research; Research Personnel; Risk; Risk Factors; Risk-Benefit Assessment; Role; Single Nucleotide Polymorphism; Stem cell transplant; Stratification; Subgroup; System; Technology; Therapeutic; Time; Training; Transplantation; Variant; biological heterogeneity; bisulfite sequencing; career; chronic graft versus host disease; chronic leukemia; clinical heterogeneity; curative treatments; cytopenia; design; epigenomics; experience; genetic variant; genome sciences; genome sequencing; genomic data; heme biosynthesis; high risk; improved; improved outcome; individual response; innovation; insertion/deletion mutation; mitochondrial DNA alteration; mitochondrial genome; modifiable risk; mortality; new therapeutic target; non-genetic; novel; novel marker; outcome prediction; patient subsets; personalized risk prediction; population based; post-transplant; precision medicine; predictive marker; professor; prognostic; prognostic model; prognostic signature; prognostic value; programs; relapse risk; risk stratification; risk/benefit ratio; statistics; stem cell homeostasis; treatment response; whole genome

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.

摘要 骨髓增生异常综合征（MDS）是一组异质性克隆性造血干细胞疾病， 其特征在于无效造血，并且在30%的患者中有进展为急性髓性白血病的趋势。 病人目前MDS的唯一治愈性疗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并发症，HCT后的死亡率很高。 常用的HCT的MDS预后模型仅考虑非遗传因素，因此不能用于预测HCT。 准确预测HCT后的结果。因此，迫切需要新的预测标志物来识别 最有可能从HCT中获益的患者。线粒体在造血细胞中起着重要作用 稳态和分化。线粒体DNA（mtDNA）的遗传和表观遗传改变可损害 线粒体功能，并在MDS中发挥病理生理作用。该职业发展奖将 为董博士提供培训和研究经验，以支持她成为一名 在综合分子流行病学的独立调查员，重点是应用最先进的 组学技术和创新的基于人群的流行病学方法，以减轻疾病负担 血液病虽然董博士在遗传学和流行病学方面受过全面的培训， 需要进一步培训HCT相关结果和表观遗传学的方法。她已经组装了一个 指导团队由主要导师Raul Urrutia博士（基因组科学主任）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; 共同导师：Wael Saber博士，急性和慢性白血病工作组教授兼科学主任 CIBMTR中专门从事HCT和MDS的委员会; Paul奥尔博士，教授和癌症中心核心 具有统计学和生物信息学专业知识的董事。利用现有的全基因组测序 来自CIBMTR的“MDS基因组学和表观遗传学研究”的数据，Dong博士将专注于线粒体 基因组，以解决上述研究差距：1）确定线粒体基因组景观 与allo-HCT后MDS结局相关; 2）定量mtDNA拷贝数并评估其相关性 与HCT后MDS结局相关; 3）鉴定与MDS结局相关的mtDNA甲基化谱 HCT后这一发现将提高我们对MDS病因学的理解，并提供更多的分子生物学证据。 HCT后MDS结局的预测因素，以帮助制定个性化的风险预测和有针对性的 治疗。