Towards Precision Medicine in Childhood Acquired Aplastic Anemia

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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.