Journal
HAEMATOLOGICA
Volume 100, Issue 1, Pages 70-76Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2014.110742
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Funding
- Collaborative Health Research Project (CHRP)
- Natural Sciences and Engineering Research Council (NSERC)
- Canadian Institutes of Health Research (CIHR)
- Nova Scotia Health Research Foundation (NSHRF)
- BHCRI
- CIBC
- CCS
- Harvey Graham Cancer Research Fund
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Cancer therapeutics is evolving to precision medicine, with the goal of matching targeted compounds with molecular aberrations underlying a patient's cancer. While murine models offer a pre-clinical tool, associated costs and time are not compatible with actionable patient-directed interventions. Using the paradigm of T-cell acute lymphoblastic leukemia, a high-risk disease with defined molecular underpinnings, we developed a zebrafish human cancer xenotransplantation model to inform therapeutic decisions. Using a focused chemical genomic approach, we demonstrate that xenografted cell lines harboring mutations in the NOTCH1 and PI3K/AKT pathways respond concordantly to their targeted therapies, patient-derived T-cell acute lymphoblastic leukemia can be successfully engrafted in zebrafish and specific drug responses can be quantitatively determined. Using this approach, we identified a mutation sensitive to.-secretase inhibition in a xenograft from a child with T-cell acute lymphoblastic leukemia, confirmed by Sanger sequencing and validated as a gain-of-function NOTCH1 mutation. The zebrafish xenotransplantation platform provides a novel cost-effective means of tailoring leukemia therapy in real time.
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