Proviral insertion indicates a dominant oncogenic role for Runx1/AML-1 in T-cell lymphoma.
The RUNX1/AML1 gene is a frequent target for chromosomal translocations in human leukemia. The biological properties of the resulting fusion products and the finding that haploinsufficiency increases the risk of developing leukemia (W-J. Song et al., Nat. Genet., 23: 166-175, 1999; M. Osata et al., Blood, 93: 1817-1824, 1999) have led to the widely held view that RUNX1 loss-of-function is a key event. However, we now report that the gene is a target for insertional mutagenesis in T-cell lymphomas of mice carrying a MYC oncogene, where promoter insertion results in overexpression without affecting the integrity of the coding sequence. Moreover, Runx1 haploinsufficiency does not accelerate lymphoma development in MYC/Runx2 transgenic or murine leukemia virus-infected mice. These findings reveal that the Runx1 gene can also act as a dominant oncogene and suggest that the involvement of the Runx gene family in human leukemia may be more widespread and complex than previously realized.
Wotton
Sandy
S
Molecular Oncology Laboratory, Institute of Comparative Medicine, University of Glasgow Veterinary School, United Kingdom.
Stewart
Monica
M
Blyth
Karen
K
Vaillant
Francois
F
Kilbey
Anna
A
Neil
James C
JC
Cameron
Ewan R
ER
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D005799:Genes, Dominant; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D009052:Leukemia Virus, Murine / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009857:Oncogenes; D011518:Proto-Oncogene Proteins; D011533:Proviruses / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors