|ZFIN ID: ZDB-PUB-141005-6|
Focused Chemical Genomics Using Zebrafish Xenotransplantation As A Pre-Clinical Therapeutic Platform For T-Cell Acute Lymphoblastic Leukemia
Bentley, V.L., Veinotte, C.J., Corkery, D.P., Pinder, J.B., LeBlanc, M.A., Bedard, K., Weng, A.P., Berman, J.N., Dellaire, G.
|Source:||Haematologica 100(1): 70-6 (Journal)|
|Registered Authors:||Bentley, Victoria, Berman, Jason, Corkery, Dale, Veinotte, Chansey|
|Keywords:||Pediatric Acute Lymphoblastic Leukemia, animal models of cancer, molecular diagnosis and prognosis, xenograft models, zebrafish models|
|PubMed:||25281505 Full text @ Haematologica|
Bentley, V.L., Veinotte, C.J., Corkery, D.P., Pinder, J.B., LeBlanc, M.A., Bedard, K., Weng, A.P., Berman, J.N., Dellaire, G. (2015) Focused Chemical Genomics Using Zebrafish Xenotransplantation As A Pre-Clinical Therapeutic Platform For T-Cell Acute Lymphoblastic Leukemia. Haematologica. 100(1):70-6.
ABSTRACTCancer 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 γ-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.