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.

抽象的 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， 其特点是造血功能无效，并且 30% 的患者有进展为急性髓系白血病的倾向 目前治疗MDS的唯一方法是异基因造血干细胞移植。 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MDS HCT预后模型仅考虑非遗传因素，无法考虑 因此，迫切需要新的预测标记来识别 HCT 后的结果。 最有可能从 HCT 中受益的患者 线粒体在造血细胞中发挥着关键作用。 线粒体 DNA (mtDNA) 的体内平衡和分化可能会受到损害。 线粒体功能并在 MDS 中发挥病理生理学作用。 为董博士提供培训和研究经验，以支持她成为一名 综合分子流行病学独立研究者，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，以减轻负担 虽然董医生接受过遗传学和流行病学方面的全面培训，但她 需要进一步接受 HCT 相关结果和表观遗传学方法的培训。 指导团队由主要导师、基因组科学主任 Raul Urrutia 博士和 精准医学中心和基因组学、表观基因组学和精准医学领域的知名领导者和两个； 共同导师：Wael Saber 博士，急性和慢性白血病工作教授兼科学主任 CIBMTR 专门从事 HCT 和 MDS 的委员会；Paul Auer 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总监。 来自CIBMTR“MDS基因组学和表观遗传学研究”的数据，董博士将重点关注线粒体 基因组来解决上述研究空白：1）确定线粒体基因组景观 与 allo-HCT 后的 MDS 结果相关；2) 量化 mtDNA 拷贝数并评估其关联 HCT 后的 MDS 结果；3) 确定与 MDS 结果相关的 mtDNA 甲基化谱 HCT 后的研究结果将提高我们对 MDS 病因的理解并提供更多分子信息。 HCT 后 MDS 结果的预测因子，有助于制定个性化风险预测和目标 治疗。