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  • Original Paper
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Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors

Oncogene volume 24, pages 2695–2704 (2005)Cite this article

Abstract

RasGRP1 is a Ras-specific exchange factor, which is activated by T-cell receptor (TCR) and promotes TCR-dependent positive selection of thymocytes. RasGRP1 is highly expressed on most T lymphocytic leukemias and is a common site of proviral insertion in retrovirus-induced murine T-cell lymphomas. We used RasGRP1 transgenic mice to determine if deregulated expression of RasGRP1 has a causative role in the development of T-cell malignancies. Thymic lymphomas occurred in three different RasGRP1 transgenic mouse lines. Thymocyte transformation correlated with high transgene expression in early stage lymphomas, indicating that deregulated RasGRP1 expression contributed to the initiation of lymphomagenesis. Expression of the positively selectable H-Y TCR accelerated lymphomagenesis in RasGRP1 transgenic mice. However, the transformed thymocytes lacked markers of positive selection and lymphomas occurred when positive selection was precluded by negative selection of the H-Y TCR. Therefore, initiation of lymphomagenesis via RasGRP1 was not associated with TCR-dependent positive selection of thymocytes. Thymic lymphomas occurred in RasGRP1 transgenic/Rag2−/− mice, demonstrating that neither TCR nor pre-TCR were required for RasGRP1-driven lymphomagenesis. The RasGRP1 transgene conferred pre-TCR-independent survival and proliferation of immature thymocytes, suggesting that deregulated expression of RasGRP1 promotes lymphomagenesis by expanding the pool of thymocytes which are susceptible to transformation.

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Acknowledgements

We are grateful to Rewa Grewal, Carolyn Bateman, Tracey Sutcliffe and others at the BCCRC Joint Animal Facility for their contributions to generating and maintaining our mice. Nastaran Mohammadi and Heather Kirk provided excellent technical assistance with the mouse genotyping. This work was supported by operating grants from the Canadian Institutes of Health Research and the Cancer Research Society to RJK, and by a CIHR doctoral research award to MBK.

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Author notes

  1. Mark B Klinger

    Present address: Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA, 94143-0414, USA

  2. Benoit Guilbault

    Present address: StemCell Technologies Inc., 570 West 7th Avenue, Vancouver, BC, Canada, V5Z 1B3

Authors and Affiliations

  1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada

    Mark B Klinger, Benoit Guilbault, Rebecca E Goulding & Robert J Kay

  2. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    Mark B Klinger, Benoit Guilbault, Rebecca E Goulding & Robert J Kay

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  1. Mark B Klinger
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Correspondence to Robert J Kay.

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Klinger, M., Guilbault, B., Goulding, R. et al. Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors. Oncogene 24, 2695–2704 (2005). https://doi.org/10.1038/sj.onc.1208334

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