A full-length Notch1 allele is dispensable for transformation associated with a provirally activated truncated Notch1 allele in Moloney MuLV-infected MMTVD/myc transgenic mice

Abstract

The Notch1 gene was previously found to be targetted by provirus insertion in a high proportion of T-cell lymphomas arising in Moloney MuLV-inoculated MMTV(D)/myc transgenic mice. Proviral activation of Notch1 was associated with overexpression of truncated Notch1, deleted of the sequences coding for the extracellular domain. The high levels of truncated Notch1 RNA and proteins in these tumors are thought to be involved in the oncogenic transformation. However, in addition to these truncated RNA and proteins, high level expression of full-length Notch1 RNA and proteins was also observed in several tumors, suggesting that they could also contribute to the transformation process. To test this hypothesis, we used a genetic approach and studied MMTV(D)/myc transgenic mice in which one of the Notch1 alleles was mutated by targeted mutagenesis (Notch1+/- mice). Heterozygote (Notch1+/-) and wild-type (Notch1+/+) transgenic mice were inoculated with Moloney MuLV and the frequency of Notch1 rearrangements was compared between both groups. Notch1 was rearranged at similar frequencies in both groups, indicating that the full-length Notch1 allele is dispensable in tumors harboring an activated Notch1 allele.