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A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC
- Source :
- Oncogene. 18:7124-7134
- Publication Year :
- 1999
- Publisher :
- Springer Science and Business Media LLC, 1999.
-
Abstract
- The Cbfa1/PEBP2 alpha A/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-mycER) and Cbfa1 was found to rescue expression of the CD2-myc transgene in pre-leukaemic 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-mycER mice showed accelerated death on induction with tamoxifen at similar rates to CD2-mycER controls. Moreover, thymocytes from preleukaemic CD2-Cbfa1-G1 mice showed reduced survival in vitro and increased sensitivity to the inhibitory effects of TGF-beta. This study demonstrates that a full-length Cbf alpha-chain gene can act as an oncogene without fusion to a heterologous protein.
- Subjects :
- Gene isoform
Cancer Research
Lymphoma
T-Lymphocytes
Transgene
T cell
Apoptosis
Core Binding Factor Alpha 1 Subunit
Mice, Transgenic
Biology
medicine.disease_cause
Proto-Oncogene Proteins c-myc
Gene product
Mice
Gene expression
Genetics
medicine
Animals
Transgenes
Molecular Biology
Oncogene
Core Binding Factors
Molecular biology
Neoplasm Proteins
Phenotype
medicine.anatomical_structure
Cancer research
Carcinogenesis
Cell Division
CD8
Transcription Factors
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....6ec6f4458381302003ef70b1e09c7d86
- Full Text :
- https://doi.org/10.1038/sj.onc.1203202