Towards Precision Medicine in Childhood Acquired Aplastic Anemia

我们的临床医生和研究人员组成的多学科团队寻求新的患者个性化方法来了解和处理儿童获得性再生障碍性贫血(AAA)，这是一种罕见但毁灭性的疾病，其特征是骨髓造血干细胞(HSC)发育不良，并伴有危及生命的出血、贫血和感染。儿童AAA被认为是通过HSCs的免疫细胞攻击发生的，但对其发病机制知之甚少，目前的治疗也不是基于机制。一些AAA患者出现克隆性造血，这通常被悲观地视为即将到来的骨髓发育不良或白血病的迹象。然而，情况可能并不总是如此，因为我们的初步研究发现，许多患有克隆性造血的AAA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占主导地位的造血克隆中存在独特的突变。因此，我们假设，AAA的克隆性造血是由突变事件导致的，这些突变事件给HSC或早期祖细胞带来了生长或生存优势，特别是在面对与疾病相关的侮辱时。我们将使用现代基因组方法在一大群AAA患者中确定这些突变的范围(目标1)，纵向跟踪患者的临床过程和遗传进化(目标2)。我们研究的几个独特方面提高了其成功的可能性：首先，我们是一支在AAA、生物信息学和基因组学/遗传学的临床管理方面拥有广泛的协同专业知识的研究团队。在费城儿童医院和宾夕法尼亚大学医院的综合儿童-成人骨髓衰竭诊所纵向跟踪所有患者的能力。最后，我们的研究将利用13年来连续从100多名AAA患者获得的大量临床上有良好注释的组织收集，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跟踪，并在整个研究过程中获取更多样本。如果成功，我们的工作将识别一组基因和基因突变，这些基因和基因突变将从分子上对AAA进行细分，以更准确地预测预后，并确定更有效的、基于机制的患者特定治疗方法。

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.