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Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies

Oncogene volume 32, pages 1066–1072 (2013)Cite this article

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Abstract

Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven ‘double-hit’ lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human ‘double-hit’ lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in ‘double-hit’ lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.

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Acknowledgements

We thank P Bak and Herman Eisen for helpful discussions and the Swanson Biotechnology Center for excellent technical support. This work was partly supported by grants from the Marble Family Foundation (to JC and MTH), Singapore-MIT Alliance for Research and Technology (to JC) and the NIH (R01-CA128803 to MTH). CPP is supported by a research fellowship of the German Research foundation. IL was supported in part by the MIT School of Science Cancer Research Fellowship, the Ludwig Academic Graduate Fellowship and the Medical Scientist Training Program (Grant Number T32GM007753 from the National Institute Of General Medical Sciences). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of General Medical Sciences or the National Institutes of Health.

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Author notes

  1. I Leskov and C P Pallasch: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    I Leskov, C P Pallasch, A Drake, B P Iliopoulou, A Souza, C-H Shen, M T Hemann & J Chen

  2. Department I of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne, Germany

    C P Pallasch, C D Schweighofer, L P Frenzel & C M Wendtner

  3. Cluster of Excellence for Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    C P Pallasch, L Abruzzo, L P Frenzel & C M Wendtner

  4. Department of Hematopathology, UT M.D. Anderson Cancer Center Houston, Houston, TX, USA

    C D Schweighofer

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  1. I Leskov
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Correspondence to M T Hemann or J Chen.

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Leskov, I., Pallasch, C., Drake, A. et al. Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies. Oncogene 32, 1066–1072 (2013). https://doi.org/10.1038/onc.2012.117

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