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.
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:
  • Amyloid Precursor Protein Secretases/antagonists & inhibitors
  • Animals
  • Antineoplastic Agents/pharmacology*
  • Cells, Cultured
  • Child
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/drug effects*
  • Embryo, Nonmammalian/metabolism
  • Enzyme Inhibitors/pharmacology
  • Fluorescent Antibody Technique
  • Genomics/methods*
  • HeLa Cells
  • Humans
  • Mutation/genetics*
  • PTEN Phosphohydrolase/genetics
  • Phosphatidylinositol 3-Kinases/genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
  • Proto-Oncogene Proteins c-akt/genetics
  • Receptor, Notch1/genetics
  • Signal Transduction
  • Transplantation, Heterologous
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed: 25281505 Full text @ Haematologica
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.