Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging.
The Runx2 (Cbfa1, Pebp2alphaA, Aml3) gene was previously identified as a frequent target for transcriptional activation by proviral insertion in T-cell lymphomas of CD2-MYC transgenic mice. We have recently shown that over-expression of the full-length, most highly expressed Runx2 isoform in the thymus perturbs T-cell development, leads to development of spontaneous lymphomas at low frequency and is strongly synergistic with Myc. To gain further insight into the relationship of Runx2 to other lymphomagenic pathways, we tested the effect of combining the CD2-Runx2 transgene either with a Pim1 transgene (E(mu)-Pim1) or with the p53 null genotype, as each of these displays independent synergy with Myc. In both cases we observed synergistic tumour development. However, Runx2 appeared to have a dominant effect on the tumour phenotype in each case, with most tumours conforming to the CD3(+), CD8(+), CD4(+/-) phenotype seen in CD2-Runx2 mice. Neonatal infection of CD2-Runx2 mice with Moloney murine leukaemia virus (Moloney MLV) also led to a dramatic acceleration of tumour onset. Analysis of known Moloney MLV target genes in these lymphomas showed a high frequency of rearrangement at c-Myc or N-Myc (82%), and a significant number at Pim1 or Pim2 (23%), and at Pal1/Gfi1 (18%). These results indicate that Runx2 makes a distinct contribution to T-cell lymphoma development which does not coincide with any of the oncogene complementation groups previously identified by retroviral tagging.
Blyth
K
K
Molecular Oncology Laboratory, University of Glasgow Veterinary School, Bearsden, Glasgow, G61 1QH, UK.
Terry
A
A
Mackay
N
N
Vaillant
F
F
Bell
M
M
Cameron
E R
ER
Neil
J C
JC
Stewart
M
M
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D018801:CD2 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D029742:Caenorhabditis elegans Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics; D005656:Fungal Proteins; D015329:Gene Rearrangement, T-Lymphocyte; D005816:Genetic Complementation Test; D015801:Helminth Proteins; D018398:Homeodomain Proteins; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000276:immunology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000472:pathogenicity; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1; D012190:Retroviridae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D013953:Thymus Neoplasms / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D018801:CD2 Antigens; D017252:CD3 Complex; D029742:Caenorhabditis elegans Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C079873:Gfi1 protein, mouse; D015801:Helminth Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; C098338:PXA1 protein, S cerevisiae; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C068665:pal-1 protein, C elegans; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1