Grants and Contracts per year
Grants and Contracts Details
Chromosomal translocation is a hallmark of pediatric leukemia, and is thought to be an initiating event in disease progression. These translocations will place a gene near a strong promoter so that the gene is highly and abnormally expressed or will create a hybrid gene by splicing two different genes together, creating a gene with an altered function. The products of translocations are known as “fusion oncoproteins”. While they are considered critical players in leukemia pathogenesis, the cellular mechanisms by which fusion oncoproteins drive transformation, leukemia onset, progression, and relapse are not defined. Genetically engineered mouse models and human cell lines are being used to assess the role of fusion oncoproteins in leukemia, but modeling many different fusion oncoproteins in mouse is cost prohibitive, and cell culture cannot be used to assess early events in leukemiagenesis. To address this critical lack in the field, we are proposing to develop zebrafish models of fusions oncoproteins in pediatric leukemia. Zebrafish disease models accurately recapitulate their human counterparts, zebrafish are inexpensive to maintain and use, and imaging techniques that are unique to zebrafish allow researchers to assess leukemia from its earliest onset. We will optimize CRISPR/Cas9-mediated gene insertion in a unique zebrafish line that is pre-disposed to homology directed repair, and provide proof-of-principle that zebrafish can be used to study fusion oncoproteins by modeling three of the most common translocations in pediatric leukemia. With this new tool in hand, researchers will be able to rapidly model many different fusion oncoproteins in pediatric cancers, define their cellular mechansims in cancer progress, and perfrom high-throughput, low cost, in vivo screens for compounds that are capable of eliminating the fusion oncoprotein phenotype
|Effective start/end date||8/1/17 → 7/31/18|
- National Cancer Institute
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