Inducible transgene expression in PDX models in vivo identifies KLF4 as therapeutic target for B-ALL
| Autor: | Wen-Hsin Liu, Tobias Herold, Paulina Mrozek-Gorska, Dagmar Pich, Kerstin Völse, Irmela Jeremias, M. Camila Melo-Narváez, Larissa Schwarzkopf, Wolfgang Hammerschmidt, Michela Carlet, Anna-Katharina Wirth |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Lymphoblast Azacitidine Biology medicine.disease_cause medicine.disease Epstein–Barr virus Minimal residual disease 3. Good health 03 medical and health sciences Leukemia 0302 clinical medicine medicine.anatomical_structure stomatognathic system KLF4 030220 oncology & carcinogenesis medicine Cancer research Stem cell B cell 030304 developmental biology medicine.drug |
| DOI: | 10.1101/737726 |
| Popis: | 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 in established patient-derived xenograft (PDX) models in vivo to fill this gap. With this technique at hand, we analyzed the role of transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive pre-clinical in vivo trials, we found that re-expression of wild type KLF4 reduced leukemia load in PDX models of B-ALL, with strongest effects after conventional chemotherapy at minimal residual disease (MRD). A non-functional KLF4 mutant had no effect in this model. Re-expressing KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. Of major translational relevance, Azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced Azacitidine-induced cell death, suggesting that Azacitidine can regulate KLF4 re-expression. These results support applying Azacitidine in patients with B-ALL to regulated KLF4 as a therapeutic option. Taken together, our novel technique allows studying the function of dysregulated genes in a highly clinic-related, translational context and testing clinically applicable drugs in a relevant pre-clinical model. |
| Databáze: | OpenAIRE |
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