The Genetics of Post-Transplant Relapse in Myeloid Malignancy

骨髓恶性肿瘤移植后复发的遗传学

基本信息

批准号：
8857124
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857124
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 Health 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 genetic predictors hematopoietic cell transplantation high risk individualized medicine insight leukemia pressure response symposium transplantation typing treatment response treatment strategy tumor

项目摘要

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后治愈（HCT）的主要障碍。尽管制备方案采用了化学疗法，放射性抗体或辅助免疫疗法的药代动力学靶向，但复发仍然是HCT后治疗衰竭的主要原因。实际上，最近的NCI赞助会议解决了HCT后复发问题，其中的结论是，需要对移植前和后移植样本进行研究以了解复发的生物学（1）。该建议解决了这个问题。因此，在AIM 1中，我们将确定造血细胞移植（HCT）的急性髓样白血病（AML）后结果的遗传预测因子。我们假设有一些遗传途径可以预测对HCT的治疗反应，而不是疾病阶段（由爆炸数和细胞遗传学定义）。因此，我们将使用mRNA和miRNA表达分析来识别区分失败患者的基因和途径，即HCT后的复发和HCT后无病的患者。这个目标的结果将使我们能够更好地风险将患者分类为不同的治疗方法，并使我们深入了解移植后推动反应的生物学机制。在AIM 2中，我们将定义最小残留疾病（MRD）和复发期间AML的遗传变化。我们开发了可以在用流式细胞术捕获的少量细胞上执行基因表达的方法。因此，我们将遵循特定目标1中发现的基因表达以及在诊断，MRD和复发中发现的特定目标1中发现的签名（如果发生的话）。这将使我们能够完善MRD检测，不仅了解疗法后仍有多少残留疾病，而且还要确定其分子特征，这对于预测复发以及选择性的空中疗法可能很重要。最后，在AIM 3中，我们将定义克隆选择在AML中的作用 HCT后复发。该目标将通过单细胞基因分型和基因表达比较诊断和复发样品，以了解复发样品与移植前疾病的样本的比较。对复发中克隆选择的上下文和程度的理解可能在调整治疗策略中很重要，以最大程度地减少选择和抗性克隆的逃脱。