Activating Notch1 mutations have been reported in human T-lineage
acute lymphoblastic leukemia (
T-ALL) and
lymphomas from genetically modified mice. We report that Notch1 is a prevalent and major mutational target in chemically induced mouse
lymphoma. The regions of the gene that are frequently mutated are the heterodimerization domain and the N-terminal
ligand-binding region, important for protein stability, and the
polypeptide rich in
proline,
glutamate,
serine and
threonine (PEST) domains, which is critical for protein degradation. Another gene, CDC4, is also involved in Notch1 degradation and shows frequent mutations. Mutations in the heterodimerization and the
ligand-binding regions may cause
ligand-independent signaling, whereas mutations preventing protein degradation result in accumulation of intracellular Notch1. We analyzed 103 chemical-induced mouse
lymphomas for mutations in the Notch1 gene using single strand conformation analysis (SSCA) and
DNA sequencing. Genetic alterations resulting in premature truncation of Notch1 were identified in 28
tumors, whereas 8 revealed alterations in the heterodimerization and 16 harbored deletions in the
ligand-binding region.
Dideoxycytidine-induced
lymphomas displayed the highest frequency of Notch1 mutations (49%), whereas in
butadiene- and
phenolphthalein-induced
tumors showed lower frequencies (26 and 10%, respectively). In total, 26 novel and 3 previously reported mutations were detected. This report shows that Notch1 is a prevalent and major mutational target for
2',3'-dideoxycytidine and
butadiene-induced
lymphoma.