A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc

Vaillant, F., Blyth, K. , Terry, A., Bell, M., Cameron, E. R. , Neil, J. and Stewart, M. (1999) A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc. Oncogene, 18(50), pp. 7124-7134. (doi: 10.1038/sj.onc.1203202) (PMID:10597314)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Cameron, Professor Ewan and Neil, Professor James and Bell, Mrs Margaret and Stewart, Dr Monica and Terry, Mrs Anne
Authors: Vaillant, F., Blyth, K., Terry, A., Bell, M., Cameron, E. R., Neil, J., and Stewart, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Oncogene
Publisher:Stockton Press
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:30 November 1999

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