Inducible transgene expression in PDX models in vivo identifies KLF4 as therapeutic target for B-ALL

• DOI: 10.1101/737726
• Publication Date: 2019-08-17T04:25:12Z
• Authors: Wen-Hsin Liu; Paulina Mrozek-Go...; Tobias Herold; Larissa Schwarzkopf; Dagmar Pich; Kerstin Völse; Anna-Katharina Wirth; M. Camila Melo-Na...; Michela Carlet; Wolfgang Hammersc...; Irmela Jeremias
• Keywords: KLF4; Azacitidine

Clinic-close methods are not available that prioritize and validate potential therapeutic targets in individual tumors from the vast bulk of descriptive expression data. We developed a novel technique to express transgenes established patient-derived xenograft (PDX) models vivo fill this gap. With at hand, we analyzed role transcription factor Krüppel-like 4 (KLF4) B-cell acute lymphoblastic leukemia (B-ALL) PDX different disease stages. In competitive pre-clinical trials, found re-expression wild type KLF4 reduced load B-ALL, with strongest effects after conventional chemotherapy minimal residual (MRD). A non-functional mutant had no effect model. Re-expressing sensitized tumor cells model towards systemic . Of major translational relevance, Azacitidine upregulated levels knockout Azacitidine-induced cell death, suggesting can regulate re-expression. These results support applying patients B-ALL regulated as option. Taken together, our allows studying function dysregulated genes highly clinic-related, context testing clinically applicable drugs relevant