Aplastic anemia (AA) is a devastating blood disorder, affecting children and adults, caused by immune attack on the bone marrow. Factors that determine recovery, relapse, and transformation to myelodysplasia in aAA remain poorly defined, and there is a dearth of studies in pediatric patients. Emerging data suggest that mutations in the bone marrow and in the pathogenic immune cells contribute to disease evolution and relapse. To study this, I will employ cutting-edge genomic techniques to characterize pathogenic mutations in aAA. These studies will improve treatment of patients with pediatric AA by allowing early detection of clonal evolution and disease progression.
In the first year of this project we used cutting-edge genetic techniques to look for new mutations and larger genetic aberrations in the bone marrow of an initial cohort of approximately thirty aplastic anemia patients at the Children’s Hospital of Philadelphia and the University of Pennsylvania. Our findings showed that the majority of aplastic anemia patients, including children, have detectable genetic changes in their bone marrow. These changes are not present in the patient’s skin, indicating that these mutations are not inherited, but rather emerge in the bone marrow in the course of the disease. New mutations can be detected as early as one year after diagnosis. The most common mutations in our initial study were those that lead to the development of Paroxysmal Nocturnal Hemoglobinuria and those that cause the loss of immune recognition. The mutations were present in a significant portion of early blood cells, indicating that in most patients, a substantial part of their blood production comes from the progeny of a single cell that acquired these genetic changes. Among the mutations identified in the study, many were in genes involved in immune response and cell growth. Based on their findings, we hypothesize that a patient’s response to treatment and their overall disease course can be affected by individual differences in the genetic make-up of their bone marrow.
In the second year of this project, we plan to validate these preliminary results in a larger number of patients. We will also follow the patients’ genetic changes over time to determine the impact of acquired mutations on prognosis and patients’ recovery. Our long-term goal is to use the knowledge of the genetic make-up of an individual patient’s bone marrow to improve the diagnosis and disease surveillance of aplastic anemia patients. We hope results of our studies will pave way for personalized treatment strategies, bringing Precision Medicine to the field of aplastic anemia. These studies would not have been possible without the generous support from the AA&MDS International Foundation.