Towards Precision Medicine in Childhood Acquired Aplastic Anemia

我们的临床医生和研究人员的多学科团队寻求新的患者个性化的方法来理解和管理儿科获得性再生障碍性贫血（aAA），一种罕见但破坏性的疾病，其特征是骨髓造血干细胞（HSC）发育不全，危及生命的出血，贫血和感染。儿科aAA被认为是通过免疫细胞攻击HSC发生的，但对发病机制知之甚少，目前的治疗方法也不是基于机制的。一些aAA患者发生克隆性造血，通常被悲观地视为即将发生骨髓增生异常或白血病的迹象。然而，情况可能并非总是如此，因为我们的初步研究已经确定了许多具有克隆造血的aAA患者，这些患者多年来一直处于健康缓解状态。 此外，这些患者中的许多人在其显性造血克隆内具有独特的突变。 因此，我们假设aAA中的克隆造血是由突变事件引起的，突变事件赋予HSC或早期祖细胞生长或存活优势，特别是在面对疾病相关损伤时。我们将使用现代基因组学方法来确定这些突变在一个大型aAA患者队列中的范围（目标1），纵向跟踪患者的临床病程和遗传进化（目标2）。我们研究的几个独特方面提高了成功的可能性：首先，我们是一个研究团队，在aAA，生物信息学和基因组学/遗传学的临床管理方面具有广泛的协同专业知识。在费城儿童医院和宾夕法尼亚大学医院的综合性儿科-成人骨髓衰竭诊所中纵向随访所有患者的能力。 最后，我们的研究将利用13年来从100多名aAA患者中连续获得的大量临床注释良好的组织集合，包括DNA和冷冻保存的皮肤，血液和骨髓细胞。 我们将继续对这些患者进行临床随访，并在整个研究期间采集额外样本。 如果成功的话，我们的工作将确定一组基因和基因突变，这些基因和基因突变将对aAA进行分子分类，以更准确地预测预后，并确定更有效的、基于机制的患者特异性疗法。

Our multidisciplinary team of clinicians and researchers seeks novel patient-individualized approaches for understanding and managing pediatric acquired aplastic anemia (aAA), a rare but devastating condition characterized by bone marrow hematopoietic stem cell (HSC) hypoplasia with life threatening bleeding, anemia and infections. Pediatric aAA is believed to occur via immune cell attack of HSCs, but little more is known about the pathogenesis and current treatments are not mechanism-based. Some patients with aAA develop clonal hematopoiesis, which is typically viewed pessimistically as a sign of impending myelodysplasia or leukemia. However, this may not always be the case, as our preliminary studies have identified numerous aAA patients with clonal hematopoiesis who have been in healthy remission for years. Moreover, many of these patients harbor unique mutations within their dominant hematopoietic clones. Thus, we hypothesize that clonal hematopoeisis in aAA results from mutational events that impart a growth or survival advantage to HSCs or early progenitors, particularly in the face of disease-associated insults. We will use modern genomic approaches to define the scope of these mutations in a large cohort of aAA patients (Aim 1), follow the clinical course and genetic evolution of the patients longitudinally (Aim 2). Several unique aspects of our study enhance its likelihood of success: First, we are a team of investigators with broad, synergistic expertise in the clinical management of aAA, bioinformatics and genomics/genetics. The ability to follow all of the patients longitudinally in a comprehensive pediatric-adult bone marrow failure clinic at The Children's Hospital of Philadelphia and The Hospital of the University of Pennsylvania. Finally, our study will utilize a large clinically well-annotated tissue collection obtained serially from over 100 aAA patients over 13 years, consisting of DNA and cryopreserved skin, blood and bone marrow cells. We will continue to follow these patients clinically and procure additional samples throughout the study. If successful, our work will identify sets of genes and gene mutations that will sub-classify aAA molecularly to predict prognosis more accurately and to identify more effective, mechanism-based patient-specific therapies.