Modeling Pediatric Leukemia in the Zebrafish to Enable Discovery of New Anti-Leukemic Compounds

Over 100 billion blood cells are generated every day from our bone marrow.  Paradoxically, these vast numbers of cells derive from an exceedingly rare population of hematopoietic stem cells (HSCs) that both self-renew and generate all blood and immune cell types for life.  The characteristics and functions of these remarkable cells are highly conserved in all vertebrate animals.  Our laboratory utilizes the unique attributes of the zebrafish embryo to study the biology of HSCs in new ways.  By creating transgenic zebrafish expressing fluorescent proteins we can now observe the behaviors of stem cells in real time in living, transparent animals.  We have recently described when and where HSCs are born in the early embryo, and have made excellent progress in understanding the genetic program required to generate these cell types.  In this proposal, we seek to better understand how normal HSCs become deranged to give rise to leukemia.  Despite great advances in the treatment of hematologic malignancies in children, pediatric leukemias harboring mutations in the Mixed-Lineage Leukemia (MLL) gene have poor prognoses and have remained refractory to all treatment strategies.  Interestingly, MLL+ leukemia initiates during fetal development in utero, since identical twins have been shown to possess identical chromosomal translocations.  We propose to model MLL+ leukemia in the zebrafish embryo to better understand how this disease initiates during development of the hematopoietic system, how deregulation of MLL affects HSC proliferation, migration and survival, and ultimately utilize this model to find new anti-cancer drugs to more effectively treat children with leukemia.