A Novel Approach to Identifying Exogenous Factors Linked to the Development of Childhood Leukemia
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and the leading cause of death from disease of American children. ALL is characterized by different genetic alterations and that represent “first hits,” which only lead to bona fide leukemia when combined with a “second hit” genetic alteration resulting from some environmental exposure. Unfortunately, studies designed to examine which external factors are linked to the development of ALL have been retrospective, comparing factors between groups of ALL patients and healthy control groups. This design limits the ability to identify a specific cause-and-effect in which an exposure leads to the development of leukemia. We recently obtained a novel genetic strain of zebrafish which had been engineered to express human leukemia genes (TEL-AML1). Like humans with this alteration, TEL-AML1 zebrafish contract leukemia at very low frequencies. We hypothesize that this rate could be significantly augmented by environmental factors analogous to the “two hit hypothesis” for leukemia. Our study will examine the impact of potential toxicants (e.g. pesticides) on the development of leukemia in the zebrafish TEL-AML1 model, and lay the foundation for large-scale high-throughput screens for other causative agents.
Tg(b-actin:EGFP-TEL-AML1) transgenic zebrafish develop leukemia. A. Quantitative PCR showed reduced expression of IgM in leukemic animals, indicative of fewer mature B cells. B-C. Blood smears from adult marrow showed that leukemic fish exhibit a significant increase in leukemic blasts.