Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia

Victoria L. Bentley, Chansey J. Veinotte, Dale P. Corkery, Jordan B. Pinder, Marissa A. Leblanc, Karen Bedard, Andrew P. Weng, Jason N. Berman, Graham Dellaire

Résultat de recherche: Articleexamen par les pairs

87 Citations (Scopus)

Résumé

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.

Langue d'origineEnglish
Pages (de-à)70-76
Nombre de pages7
JournalHaematologica
Volume100
Numéro de publication1
DOI
Statut de publicationPublished - 2015

Note bibliographique

Publisher Copyright:
© 2014 Ferrata Storti Foundation.

ASJC Scopus Subject Areas

  • Hematology

Empreinte numérique

Plonger dans les sujets de recherche 'Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia'. Ensemble, ils forment une empreinte numérique unique.

Citer