title: Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.
abstract: T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.
authors: Department of Pathology, University of California-San Francisco, USA.
authors: Kuang-Yu
authors: KY
authors: Jen
authors: Ihn Young
authors: IY
authors: Song
authors: Karl Luke
authors: KL
authors: Banta
authors: Di
authors: D
authors: Wu
authors: Jian-Hua
authors: JH
authors: Mao
authors: Allan
authors: A
authors: Balmain
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000473:pathology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics*; D013953:Thymus Neoplasms / Q000209:etiology* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases