Towards Precision Medicine in Childhood Acquired Aplastic Anemia

描述（由申请人提供）：我们的多学科临床医生和研究人员团队寻求新的患者个性化方法来理解和管理儿童获得性再生障碍性贫血（aAA），这是一种罕见但具有破坏性的疾病，其特征是骨髓造血干细胞（HSC）发育不全，并伴有危及生命的出血、贫血和感染。儿童aAA被认为是通过造血干细胞的免疫细胞攻击发生的，但对其发病机制知之甚少，目前的治疗方法也不是基于机制的。一些aAA患者出现克隆性造血，这通常被悲观地视为即将发生骨髓增生异常或白血病的征兆。然而，这可能并不总是如此，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，他们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中都有独特的突变。因此，我们假设aAA中的克隆造血是由突变事件引起的，这些突变事件赋予造血干细胞或早期祖细胞生长或生存优势，特别是在面对疾病相关的损伤时。我们将使用现代基因组学方法在大量aAA患者队列中定义这些突变的范围（目标1），纵向跟踪患者的临床过程和遗传进化（目标2），并通过遗传操作和患者来源的诱导多能干细胞（iPSCs）的体外造血分化研究aAA相关获得性突变的功能后果（目标3）。我们的研究有几个独特的方面提高了其成功的可能性：首先，我们是一个有成就的研究团队，在aAA的临床管理、生物伦理学、基因组学/遗传学、造血和多能干细胞生物学方面具有广泛的协同专业知识。其次，M. Bessler（首席PI）在费城儿童医院和宾夕法尼亚大学医院的儿童-成人骨髓衰竭综合诊所纵向跟踪所有患者。最后，我们的研究将利用13年来从100多名aA患者连续获得的大量临床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。Bessler博士（首席PI）将继续对这些患者进行临床随访，并在整个研究过程中获取额外的样本。如果成功，我们的工作将确定一系列基因和基因突变，这些基因和突变将对aAA进行分子亚分类，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治疗方法。

DESCRIPTION (provided by applicant): 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) and study the functional consequences of the aAA associated acquired mutations through genetic manipulation and in vitro hematopoietic differentiation of patient-derived induced pluripotent stem cells (iPSCs) (Aim 3). Several unique aspects of our study enhance its likelihood of success: First, we are a team of accomplished investigators with broad, synergistic expertise in the clinical management of aAA, bioethics, genomics/genetics, hematopoeisis and pluripotent stem cell biology. Second, M. Bessler (lead PI) follows 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 aA patients over 13 years, consisting of DNA and cryopreserved skin, blood and bone marrow cells. Dr. Bessler (lead PI) will continue to follow these patients clinically and procure additionl 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.