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Liu, W.-H. ; Mrozek-Gorska, P. ; Wirth, A.-K. ; Herold, T. ; Schwarzkopf, L. ; Pich, D. ; Völse, K. ; Melo-Narváez, C. ; Carlet, M. ; Hammerschmidt, W. ; Jeremias, I.

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

Biomark. Res. 8:46 (2020)

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	Open Access Gold

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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 Kruppel-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.

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Publication type Article: Journal article

Document type Scientific Article

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Keywords Pdx Models Of Acute Leukemia ; Inducible Transgene Expression ; Klf4 ; Azacitidine; Dna-methylation; Cancer; Leukemia; Cells; Kruppel-like-factor-4; Inactivation; Xenografts; Suppresses; Leukocytes; Lymphoma

e-ISSN 2050-7771

Journal Biomarker Research

Quellenangaben Volume: 8, Issue: 1, Article Number: 46

Publisher BMC

Publishing Place London

Non-patent literature Publications

Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Research Unit Gene Vector (AGV)

Grants National Cancer Institute
Mildred Scheel Professorship by German Cancer Aid
German Research Foundation (DFG)
Collaborative Research Center 1243
Bettina Brau Stiftung
Dr. Helmut Legerlotz Stiftung.
Helmholtz Zentrum Munchen
Deutsche Forschungsgemeinschaft
Deutsche Krebshilfe
European Research Council Consolidator Grant