The Genetics of Post-Transplant Relapse in Myeloid Malignancy

骨髓恶性肿瘤移植后复发的遗传学

• 批准号: 8579777
• 负责人: Jerald Patrick Radich
• 金额: $ 36.52万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579777
• 关键词: Accounting; Acute Myelocytic Leukemia; Address; Antibodies; Biological; Biology; Blast Cell; Cell Count; Cells; Characteristics; Clinical; Complement; Cytogenetics; Detection of Minimal Residual Disease; Diagnosis; Diagnostic; Disease; Donor person; Drug Kinetics; Failure; Flow Cytometry; Gene Expression; Gene Expression Profile; Genes; Genetic; Genotype; Hematologic Neoplasms; Hematopoietic stem cells; Heterogeneity; Homologous Transplantation; Immunotherapy; Innovative Therapy; Learning; Messenger RNA; Methods; MicroRNAs; Minority; Molecular; Mutation; Myeloproliferative disease; Outcome; Pathway interactions; Patients; Population; Protocols documentation; Radioactive; Regimen; Relapse; Research; Residual Neoplasm; Residual Tumors; Resistance; Risk; Role; Sampling; Staging; Stratification; Time; Transplant-Related Disorder; Transplantation; Treatment Failure; Work; chemotherapy; hematopoietic cell transplantation; high risk; insight; leukemia; pressure; public health relevance; response; symposium; transplantation typing; treatment response; treatment strategy; tumor

DESCRIPTION (provided by applicant): Relapse remains the major obstacle to cure following hematopoietic cell transplantation (HCT). Despite preparative regimens employing pharmacokinetic targeting of chemotherapy, radioactive antibodies, or adjunctive immunotherapy, relapse remains the leading cause of treatment failure following HCT. Indeed, a recent NCI sponsored conference addressed the problem of relapse post-HCT, and among the conclusions were that studies of pre- and post-transplant samples needed to be performed to understand the biology of relapse (1). This proposal addresses this issue. Thus in Aim 1 we will determine the genetic predictors of outcome following hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We hypothesize that there are genetic pathways that predict treatment response to HCT independent of disease stage (defined by blast count and cytogenetics). Thus, we will use mRNA and miRNA expression analysis to identify genes and pathways that distinguish patients who fail, i.e. relapse after HCT and patients who are disease-free following HCT. The results of this aim will allow us to better risk stratify patients to diffeent treatment approaches, as well as give us insight into the biological mechanisms that drive response following transplantation. In Aim 2 we will define the genetic changes in AML during minimal residual disease (MRD) and relapse. We have developed methods that can perform gene expression on small numbers of cells captured with flow cytometry. Thus, we will follow the gene expression and of the signature discovered in Specific Aim 1, as well mutational genotype, at diagnosis, MRD, and relapse (if this occurs). This will allow us to refine MRD detection to understand not only how much residual disease remains post-therapy, but define its molecular characteristics, which likely will be important to both predicting relapse, as well as selective pre- emptive therapy. Lastly, in Aim 3 we will define the role of clonal selection in AML post-HCT relapse. This aim will compare diagnostic and relapse samples by single cell genotyping and gene expression to understand how the relapsed sample compares to that of the pre-transplant disease. An understanding of the context and extent of clonal selection in relapse may prove important in tailoring treatment strategies to minimize selection and the escape of resistant clones.

描述（由申请人提供）：复发仍然是造血细胞移植（HCT）后治愈的主要障碍。尽管准备方案采用化疗、放射性抗体或免疫治疗的药代动力学靶向，但复发仍然是HCT后治疗失败的主要原因。事实上，最近NCI赞助的会议讨论了HCT后复发的问题，结论之一是需要进行移植前和移植后样本的研究以了解复发的生物学（1）。本提案涉及这一问题。因此，在目标1中，我们将确定造血细胞移植（HCT）治疗急性髓系白血病（AML）后结局的遗传预测因子。我们假设存在预测HCT治疗反应的遗传途径，与疾病分期（由原始细胞计数和细胞遗传学定义）无关。因此，我们将使用mRNA和miRNA表达分析来鉴定区分失败的患者（即HCT后复发的患者）和HCT后无病的患者的基因和途径。这一目标的结果将使我们能够更好地对患者进行风险分层，以采用有利的治疗方法，并使我们深入了解移植后驱动反应的生物学机制。在目标2中，我们将定义AML在微小残留病（MRD）和复发期间的遗传变化。我们已经开发出可以在用流式细胞术捕获的少量细胞上进行基因表达的方法。因此，我们将在诊断、MRD和复发（如果发生）时跟踪基因表达和特异性目标1中发现的特征，以及突变基因型。这将使我们能够完善MRD检测，不仅了解治疗后残留的疾病数量，而且确定其分子特征，这可能对预测复发以及选择性先发制人治疗都很重要。最后，在目标3中，我们将定义克隆选择在AML中的作用。 HCT后复发。这一目标将通过单细胞基因分型和基因表达来比较诊断和复发样本，以了解复发样本与移植前疾病的样本相比如何。了解复发中克隆选择的背景和程度可能对定制治疗策略以最大限度地减少耐药克隆的选择和逃逸非常重要。