title: Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia.
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.
authors.affiliation: Pathology, Dalhousie University, Halifax, NS.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bentley
authors.affiliation: IWK Health Centre, Halifax, NS.
authors.forename: Chansey J
authors.initials: CJ
authors.lastname: Veinotte
authors.affiliation: Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Corkery
authors.affiliation: Pathology, Dalhousie University, Halifax, NS.
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Pinder
authors.affiliation: Pathology, Dalhousie University, Halifax, NS.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: LeBlanc
authors.affiliation: Pathology, Dalhousie University, Halifax, NS.
authors.forename: Karen
authors.initials: K
authors.lastname: Bedard
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
authors.affiliation: IWK Health Centre, Halifax, NS Pediatrics and Microbiology & Immunology Dalhousie University, Halifax, NS, Canada dellaire@dal.ca jason.berman@iwk.nshealth.ca.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
authors.affiliation: Pathology, Dalhousie University, Halifax, NS Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS dellaire@dal.ca jason.berman@iwk.nshealth.ca.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D023281:Genomics / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053829:Amyloid Precursor Protein Secretases