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.

Public Health Relevance

We are a group of multidisciplinary experts seeking to improve the understanding and treatment of childhood acquired aplastic anemia (aAA), a disease in which the bone marrow cannot produce enough blood cells, resulting in life threatening bleeding, anemia and infections. We will combine our skills and technologies in clinical medicine, modern genetics, stem cell biology and blood formation (hematopoiesis) to better diagnose and treat aAA in ways that are uniquely tailored for each patient.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK103001-02
Application #
8915167
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M4))
Program Officer
Bishop, Terry Rogers
Project Start
2014-09-01
Project End
2017-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
2
Fiscal Year
2015
Total Cost
$559,998
Indirect Cost
$226,666
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Babushok, Daria V; Stanley, Natasha L; Morrissette, Jennifer J D et al. (2018) Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32. Leukemia 32:2720-2723
Sarthy, Jay; Zha, Ji; Babushok, Daria et al. (2018) Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype. Blood Adv 2:120-125
Babushok, Daria V; Duke, Jamie L; Xie, Hongbo M et al. (2017) Somatic HLA Mutations Expose the Role of Class I-Mediated Autoimmunity in Aplastic Anemia and its Clonal Complications. Blood Adv 1:1900-1910
Peslak, Scott A; Olson, Timothy; Babushok, Daria V (2017) Diagnosis and Treatment of Aplastic Anemia. Curr Treat Options Oncol 18:70
Nguyen-McCarty, Michelle; Klein, Peter S (2017) Autophagy is a signature of a signaling network that maintains hematopoietic stem cells. PLoS One 12:e0177054
Bhavanasi, Dheeraj; Wen, Kwun Wah; Liu, Xiaolei et al. (2017) Signaling mechanisms that regulate ex vivo survival of human acute myeloid leukemia initiating cells. Blood Cancer J 7:636
Stanley, Natasha; Olson, Timothy S; Babushok, Daria V (2017) Recent advances in understanding clonal haematopoiesis in aplastic anaemia. Br J Haematol 177:509-525
Babushok, Daria V; Stanley, Natasha; Xie, Hongbo M et al. (2017) Clonal Replacement Underlies Spontaneous Remission in Paroxysmal Nocturnal Haemoglobinuria. Br J Haematol 176:487-490
Betensky, Marisol; Babushok, Daria; Roth, Jacquelyn J et al. (2016) Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia. Cancer Genet 209:1-10
Liu, Wei Ping; Wang, Xiao Pei; Zheng, Wen et al. (2016) Hepatitis B virus reactivation after withdrawal of prophylactic antiviral therapy in patients with diffuse large B cell lymphoma. Leuk Lymphoma 57:1355-62

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