Open AccessFocused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia
Author(s) -
Victoria L. Bentley,
Chansey J. Veinotte,
Dale Corkery,
Jordan Pinder,
Marissa A. LeBlanc,
Karen Bedard,
Andrew P. Weng,
Jason N. Berman,
Graham Dellaire
Publication year - 2014
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2014.110742
Subject(s) - zebrafish , xenotransplantation , leukemia , crispr , cancer research , cancer , lymphoblastic leukemia , computational biology , pi3k/akt/mtor pathway , medicine , sanger sequencing , genome editing , mutation , synthetic lethality , biology , bioinformatics , immunology , transplantation , gene , genetics , signal transduction , mutant
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.