Characterizing the Developmental Context of Pediatric Leukemia
Leukemia is the most common cancer in children, accounting for almost 1 out of 3 cancers. Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells and is the leading cause of childhood leukemic mortality. There is a great need to improve the outcome of children who are diagnosed with AML by developing better-targeted treatment options. Although both children and adults are affected by AML, studies indicate that the specific genetic mutations present in childhood and adult leukemia are different. Because all AMLs originate in stem and progenitor blood cells, we hypothesize that the developmental state of the initiating cell in leukemia could play an essential role in the leukemic transformation. We are interested in investigating why certain mutations are able to initiate leukemia in children but not in adults and for this we are utilizing two childhood leukemia models that we recently developed. First, we will utilize a model of Down syndrome associated leukemia. Children with Down syndrome, who have an extra copy of chromosome 21, have a 150-fold increased risk of developing AML. Interestingly, Down syndrome associated leukemia is driven by distinct mutations in the gene GATA1 and mutations in genes of the cohesin complex, a mutational pattern not observed in adult AML. Secondly, we will utilize a model of leukemia with NUP98-NSD1 gene fusions, which are predominantly seen in childhood cases and is known to be therapy resistant. Using these two models, we aim to characterize the developmental context of leukemia initiation.
The overall vision of the project is to understand the earliest steps of how and why childhood AML initiates and to use this knowledge to innovate new therapeutic options. In order to understand the leukemic development in children, we are proposing to use CRISPR/Cas9 technology in human primary blood stem cells to model the leukemic disease in mice. For this, we are introducing the same mutations observed in leukemic patients, such as in GATA1 and cohesin genes for Down syndrome associated AML and NUP98-NSD1 for therapy resistant childhood AML, into human primary blood stem cells and, through this, model the steps of leukemia initiation. By utilizing blood stem cells from either young or adult individuals, we will systematically profile the effect of the developmental state towards leukemic transformation. This will allow us to draw a comprehensive map of which genetic mutations in which cell types are able to induce leukemia in children versus adults. Importantly, with this model in hand, we will be able to characterize the molecular mechanism that is responsible for leukemic susceptibility. We believe that this approach will allow us to identify novel therapeutic targets against Down syndrome associated AML and NUP98-NSD1 induced AML. Our long-term goal is to discover new drug targets in order to directly improve the outcome of children with AML in the clinic.