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Expression of Exogenous Cytokine in Patient-derived Xenografts via Injection with a Cytokine-transduced Stromal Cell Line
Published on: May 10, 2017
Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL
Wen-Hsin Liu1, Paulina Mrozek-Gorska2, Anna-Katharina Wirth1
1Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Marchioninistraße 25, 81377 Munich, Germany.
Background:
Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data.
Methods:
We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap.
Results:
With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that 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 the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4.
Conclusion:
Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
Insights
This study shows that re-expressing Krüppel-like factor 4 (KLF4) in patient-derived xenograft models of B-cell acute lymphoblastic leukemia (B-ALL) reduces leukemia load and sensitizes cells to chemotherapy. Azacitidine upregulates KLF4, suggesting its therapeutic potential in B-ALL.
Area of Science:
- Oncology
- Molecular Biology
- Translational Research
Background:
- Lack of methods to prioritize and validate therapeutic targets from tumor expression data.
- Need for clinically relevant models to study gene function in individual tumors.
Purpose of the Study:
- To establish inducible transgene expression in patient-derived xenograft (PDX) models.
- To investigate the role of Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL).
- To link KLF4 function to clinically available drugs for personalized treatment.
Main Methods:
- Established inducible transgene expression in patient-derived xenograft (PDX) models.
- Analyzed KLF4 function in B-ALL PDX models at different disease stages.
- Conducted preclinical in vivo trials comparing wild-type KLF4 re-expression with a nonfunctional mutant.
Main Results:
- Re-expression of wild-type KLF4 reduced leukemia load in B-ALL PDX models, particularly in minimal residual disease (MRD) after chemotherapy.
- KLF4 re-expression sensitized tumor cells to chemotherapy in vivo.
- Azacitidine upregulated KLF4 levels, and KLF4 knockout reduced azacitidine-induced cell death, indicating azacitidine regulates KLF4.
Conclusions:
- Genetic engineering of PDX models facilitates examination of dysregulated gene function in a translational context.
- This approach enables selection of therapeutic targets for individual tumors.
- Linking gene function to available drugs like azacitidine can facilitate personalized B-ALL treatment.
