PUBLICATION
Focused Chemical Genomics Using Zebrafish Xenotransplantation As A Pre-Clinical Therapeutic Platform For T-Cell Acute Lymphoblastic Leukemia
- Authors
- 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.
- ID
- ZDB-PUB-141005-6
- Date
- 2015
- 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
- MeSH Terms
-
- Child
- Transplantation, Heterologous
- Genomics/methods*
- Proto-Oncogene Proteins c-akt/genetics
- Cells, Cultured
- Zebrafish/genetics*
- Zebrafish/growth & development
- Zebrafish/metabolism
- Humans
- PTEN Phosphohydrolase/genetics
- Signal Transduction
- Receptor, Notch1/genetics
- Mutation/genetics*
- Disease Models, Animal
- Phosphatidylinositol 3-Kinases/genetics
- Fluorescent Antibody Technique
- Antineoplastic Agents/pharmacology*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
- HeLa Cells
- Amyloid Precursor Protein Secretases/antagonists & inhibitors
- Drug Resistance, Neoplasm
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Enzyme Inhibitors/pharmacology
- Animals
- PubMed
- 25281505 Full text @ Haematologica
Citation
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.
Abstract
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping