The Genetics of Post-Transplant Relapse in Myeloid Malignancy

描述(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。尽管准备方案采用了药物动力学靶向化疗、放射性抗体或辅助免疫治疗，但复发仍然是HCT后治疗失败的主要原因。事实上，最近NCI主办的一次会议讨论了HCT后复发的问题，其中的结论之一是，需要对移植前和移植后样本进行研究，以了解复发的生物学(1)。这项建议解决了这个问题。因此，在目标1中，我们将确定急性髓系白血病(AML)造血细胞移植(HCT)后预后的遗传预测因素。我们假设，存在独立于疾病阶段(由原始细胞计数和细胞遗传学定义)来预测HCT治疗反应的遗传途径。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后复发和HCT后无病患者。这一目标的结果将使我们能够更好地对患者进行不同治疗方法的风险分层，并使我们深入了解驱动移植后反应的生物学机制。在目标2中，我们将定义AML在微小残留病(MRD)和复发期间的基因变化。我们已经开发出一种方法，可以在用流式细胞仪捕获的少量细胞上进行基因表达。因此，我们将跟踪在诊断、MRD和复发(如果发生这种情况)时的基因表达和在特定目标1中发现的特征，以及突变的基因型。这将使我们能够改进MRD检测，不仅了解治疗后残留疾病的数量，而且定义其分子特征，这可能对预测复发以及选择性预防性治疗都很重要。最后，在目标3中，我们将定义克隆选择在AML中的作用 红细胞压积后复发。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比较情况。了解复发性克隆选择的背景和程度，对于制定治疗策略，最大限度地减少选择和耐药克隆的逃逸，可能是很重要的。

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.