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Genetic analysis of chemoresistance in primary murine lymphomas

Nature Medicine volume 6, pages 1029–1035 (2000)Cite this article

Abstract

Understanding the basis of chemoresistance is a principal goal of molecular oncology. We have exploited a murine lymphoma model and retroviral gene transfer to rapidly generate a series of spontaneous tumors differing only in a gene of interest, and subsequently studied the impact of the test gene on the treatment sensitivity of tumors at their natural site. We demonstrate that the Bcl-2 oncoprotein produces multi-drug resistance when assessed in primary lymphomas in vivo. In contrast, this effect was dramatically reduced when the primary lymphomas were subjected to long-term culture, and completely missed in the standard clonogenic survival assay. This model highlights the importance of physiological test systems to address the complexity of clinical drug resistance and provides a novel strategy to evaluate compounds targeting specific genetic lesions.

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Figure 1: Short-term impact of Bcl-2 over-expression on anti-cancer drug response in vitro.
Figure 2: Bcl-2 over-expression and chemotherapy in clonogenic assays.
Figure 3: Reconstitution of Eμ-myc lymphomas following retroviral infection Spontaneous cell death in lymph-node sections from a primary lymphoma and its transplanted derivatives without intermediate culturing (‘uninfected’), and after MSCV-ctrl or MSCV-bcl2 infection assessed by H&E (top; ×1000 magnification) and TUNEL staining (middle; ×200).
Figure 4: Short-term drug response of virtually infected Eμ-myc lymphomas in vivo.
Figure 5: Long-term treatment response of mice harboring virally infected Eμ-myc lymphomas.

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Acknowledgements

We thank A.W. Harris for the Eμ-myc transgenic mice, C.J. Sherr for the T220-29 cells, W.S. Pear for the MSCV-IRES-GFP construct, K. Sokol and C. Cordon-Cardo for histopathology, S. Lee, M.E. McCurrach, J. Fridman, G. Ferbeyre and M. Narita for helpful comments, and L. Bianco and the CSHL Animal Facility for technical assistance. Supported by grants from the American Cancer Society (RPG-99-200-01-LBC) and the Laurie Strauss Leukemia Foundation (S.W.L.). C.A.S. is a Dr. Mildred Scheel Cancer Foundation fellow and S.W.L. is a Rita Allen Foundation Scholar.

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  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, 11724, New York, USA

    Clemens A. Schmitt, Christine T. Rosenthal & Scott W. Lowe

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Correspondence to Scott W. Lowe.

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Schmitt, C., Rosenthal, C. & Lowe, S. Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med 6, 1029–1035 (2000). https://doi.org/10.1038/79542

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