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A novel conditional NPM-ALK-driven model of CD30+ T-cell lymphoma mediated by a translational stop cassette

Oncogene volume 39, pages 1904–1913 (2020)Cite this article

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Abstract

Targeted expression of transgenes is essential for the accurate representation of human disease in in vivo models. Current approaches to generate conditional transgenic mouse models are cumbersome and not amenable to high-throughput analysis since they require de novo generation and characterization of genetically modified mice. Here we describe a new system for lineage-restricted expression of transgenes based on a retroviral vector incorporating a translational stop cassette flanked by loxP recombination sites. Conditional transgene expression in chimeric mice is achieved by retroviral infection and transplantation of hematopoietic stem cells (HSC) derived from transgenic mice expressing Cre-recombinase from a lineage-specific promoter. For validation, we directed expression of NPM-ALK, the fusion oncogene driving a subset of anaplastic large cell lymphoma (ALCL), to T-cells by infecting hematopoietic stem cells from Lck-Cre-transgenic mice with a retroviral construct containing the NPM-ALK cDNA preceded by a translational stop cassette. These mice developed T-cell lymphomas within 12–16 weeks, featuring increased expression of the ALCL hallmark antigen CD30 as well as other cytotoxic T-cell markers, similar to the human disease. The new model represents a versatile tool for the rapid analysis of gene function in a defined lineage or in a developmental stage in vivo.

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Funding

This work was in part funded by the European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network Grant No 675712 (ALI and TP) and by the German Research Council (DFG) TRR54 grant No 34712712 (JD).

Author information

Author notes

  1. These authors contributed equally: Khalid Shoumariyeh, Nicolas Schneider, Justus Duyster, Cornelius Miething

Authors and Affiliations

  1. Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany

    Khalid Shoumariyeh, Teresa Poggio, Pia Veratti, Sophia Ehrenfeld, Desiree M. Redhaber, Robin Khan, Dietmar Pfeifer, Cathrin Klingeberg, Stefanie Kreutmair, Anna L. Illert, Justus Duyster & Cornelius Miething

  2. German Cancer Consortium (DKTK), partner site Freiburg, 79106, Freiburg, Germany

    Khalid Shoumariyeh, Pia Veratti, Sophia Ehrenfeld, Desiree M. Redhaber, Stefanie Kreutmair, Anna L. Illert, Justus Duyster & Cornelius Miething

  3. Department of Hematology, Oncology & Stem Cell Transplantation, Klinikum rechts der Isar, Technical University Munich, 81675, Munich, Germany

    Nicolas Schneider

  4. Faculty of Biology, Albert Ludwigs University of Freiburg, 79104, Freiburg, Germany

    Teresa Poggio, Sophia Ehrenfeld & Desiree M. Redhaber

  5. German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Pia Veratti, Sophia Ehrenfeld, Desiree M. Redhaber, Anna L. Illert, Justus Duyster & Cornelius Miething

  6. Institute of Pathology, Ludwig Maximilians University of Munich, 81377, Munich, Germany

    Martina Rudelius

  7. Department of Pathology, University Hospital Tübingen, 72076, Tübingen, Germany

    Leticia Quintanilla-Martinez & Falko Fend

Authors
  1. Khalid Shoumariyeh
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  2. Nicolas Schneider
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  3. Teresa Poggio
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  4. Pia Veratti
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  6. Desiree M. Redhaber
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  7. Robin Khan
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  8. Dietmar Pfeifer
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  9. Cathrin Klingeberg
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  12. Leticia Quintanilla-Martinez
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  13. Falko Fend
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  14. Anna L. Illert
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  15. Justus Duyster
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  16. Cornelius Miething
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Contributions

KS, NS, and CM performed experiments, analyzed data, and participated in writing the paper; PV and DP performed microarray experiments; SE and DMR analyzed flow cytometry data and helped write the paper; TP, CK, and SK performed mouse experiments and analyzed data; RK performed cell culture experiments and analyzed data; MR, LQM, and FF. performed immunohistochemical stainings; ALI supervised mouse experiments; JD and CM designed the study, planned experiments, analyzed data, and wrote the paper.

Corresponding author

Correspondence to Cornelius Miething.

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Shoumariyeh, K., Schneider, N., Poggio, T. et al. A novel conditional NPM-ALK-driven model of CD30+ T-cell lymphoma mediated by a translational stop cassette. Oncogene 39, 1904–1913 (2020). https://doi.org/10.1038/s41388-019-1058-1

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