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  • Original Paper
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A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC

Oncogene volume 18, pages 7124–7134 (1999)Cite this article

Abstract

The Cbfa1/PEBP2αA/AML3 gene plays an essential role in osteogenesis but is also expressed in the T-cell lineage where it has been implicated in lymphoma development as a target for retroviral insertional mutagenesis. As lymphoma cells with til-1 insertion express at least five distinct Cbfa1 isoforms, it is important to establish which, if any, have intrinsic oncogenic potential. We have generated transgenic mice in which the most abundant lymphoma isoform (G1/p57) is expressed under the control of the CD2 locus control region. Co-precipitation analysis of transgenic thymus revealed high levels of Cbfa1 protein in an abundant complex containing the binding cofactor Cbfb. CD2-Cbfa1-G1 mice displayed abnormal T-cell development, with a pronounced skew towards CD8 SP cells in the thymus and developed a low incidence of spontaneous lymphomas (6% at 12 months) with cells of similar phenotype. Strongly synergistic tumour development was seen when CD2-Cbfa1-G1 mice were crossed with lines carrying myc transgenes (CD2-myc or tamoxifen-regulatable CD2-mycERTM) and Cbfa1 was found to rescue expression of the CD2-myc transgene in preleukaemic mice. However, synergy did not appear to be due to a dominant block of myc-induced apoptosis by Cbfa1 as explanted primary tumours and cell lines from CD2-Cbfa1-G1/CD2-mycERTM mice showed accelerated death on induction with tamoxifen at similar rates to CD2-mycERTM controls. Moreover, thymocytes from preleukaemic CD2-Cbfa1-G1 mice showed reduced survival in vitro and increased sensitivity to the inhibitory effects of TGF-β. This study demonstrates that a full-length Cbf α-chain gene can act as an oncogene without fusion to a heterologous protein.

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Acknowledgements

The mouse monoclonal anti-human Cbfb antibody was a generous gift from N Speck and T Stacey (Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire, USA). The human CD2 minigene vector VA hCD2 was a kind gift from D Kioussis (NIMR, Mill Hill, London, UK). We are grateful to the Cancer Research Campaign and the Leukaemia Research Fund for their support of our research.

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Authors and Affiliations

  1. Department of Veterinary Pathology, Molecular Oncology Laboratory, University of Glasgow Veterinary School, Bearsden Road, G61 1QH, UK

    François Vaillant, Karen Blyth, Anne Terry, James Neil & Monica Stewart

  2. Division of Veterinary Clinical Studies, University of Glasgow Veterinary School, Bearsden Road, G61 1QH, UK

    Karen Blyth, Margaret Bell & Ewan R Cameron

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  1. François Vaillant
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Vaillant, F., Blyth, K., Terry, A. et al. A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC. Oncogene 18, 7124–7134 (1999). https://doi.org/10.1038/sj.onc.1203202

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