We study the mechanisms of pathogenesis of early-onset blood cancers in children and young adults. We focus on myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemias in the context of germline leukemia predisposition conditions, such as GATA2 deficiency and RUNX1-familial platelet disorder (RUNX1-FPD). Almost all germline leukemia predisposition conditions have been associated with precocious clonal hematopoiesis (CH), a pre-malignant blood state with asymmetric growth of blood stem cells with acquired mutations. Furthermore, the type of acquired mutations in a given condition is unique, differing not only from the aging-associated CH genes but also from other germline conditions. Our science is directly inspired and shaped by such observations in human disease. We use primary human disease specimens, primary human blood stem cells and preclinical zebrafish in vivo model systems for our studies.

With aging, acquired genetic mutations in a single blood stem cell may lead to its selective expansion over wildtype cells, resulting in a state of clonal hematopoiesis (CH). Although blood production is largely intact, CH is associated with increased inflammation, risk of hematologic cancers, cardiovascular disease, and other inflammatory diseases. CH is potentially transmissible through a hematopoietic stem cell transplantation (SCT). The incidence of donor CH and its persistence in pediatric recipients of haploidentical SCT is unknown. As prevalence of CH increases with aging, we focus on pediatric recipients of SCT from related haploidentical adult donors who were 18-year-old or greater at the time of donation. Our study aims to define incidence of donor CH in pediatric SCT and evaluate for persistence of donor CH in recipients using post-SCT marrow or blood samples. What are the effects of donor CH in pediatric patients with malignant blood diseases? How about those receiving SCT for non-malignant blood and immune disorders?

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is one of the leading causes of mortality in children. While therapy has improved, chemotherapy leads to significant morbidities. We want to deepen our understanding of the origin and pathogenesis of the disease to be able to predict and prevent disease onset in high-risk groups of children. One of the most common genetic lesions in B-ALL, the ETV6::RUNX1 (E/R) fusion, has been detected in up to 6.5% of healthy newborns, strongly suggesting the origin of disease in utero that undergoes further leukemogenic alteration postnatally. It is not known what causes these clones to form and grow. Using cord blood cells and a DNA-based fusion detection method called GIPFEL (Genomic Inverse PCR for Exploration of Ligated Breakpoints), we focus on perinatal factors that are associated with pre-malignant fusion positive clonal hematopoiesis.