Loss of TRP53 (p53) accelerates tumorigenesis and changes the tumor spectrum of SJL/J mice

Abstract

Known as the guardian of the genome, transformation-related protein 53 (TRP53)is a well -known tumor suppressor. Here, we describe a novel TRP53 deficient mouse model on a tumor prone background-SJL/J mice. The absence of TRP53 (TRP53 nullizygosity) leads to a shift in the tumor spectrum from a non-Hodgkin's-like disease to thymic lymphomas and testicular teratomas at a very rapid tumor onset averaging ~12 weeks of age. In haplotype studies, comparing tumor prone versus tumor resistant Trp53 null mouse strains, we found that other tumor suppressor, DNA repair and/or immune system genes modulate tumor incidence in TRP53 null strains, suggesting that even a strong tumor suppressor such as TRP53 is modulated by genetic background. Due to their rapid development of tumors, the SJL/J TRP53 null mice generated here can be used as an efficient chemotherapy or immunotherapy screening mouse model.

Methods to study xenografted human cancer in genetically diverse mice

“…For instance in GEMMs (GeneScally Engineered Mouse Models), studies have shown differences among inbred Trp53-deficient strains in the length of Sme required for the development of malignancy: In the 129S1/SvImJ Trp53-/and C57BL6/J Trp53-/-(p53 null) strains, mice develop neoplasias between 18-20 weeks (Donehower et al, 1992;Jacks et al, 1994;Olive et al, 2004). However, BALB/cJ Trp53-/mice show neoplasias by 15 weeks, and in our studies of the tumor-prone SJL/J Trp53-/-, mice have neoplasias by 12 weeks (Branca et al, 2020;Kuperwasser et al, 2000). One would predict that a null mutaSon that completely removes the Trp53 protein (p53 in human) ¾a criScal tumor suppressor and apoptosis regulator¾would not be influenced by the strain background, since cell-cycle and apoptosis genes are conserved among mouse strains (Lozano and Levine, 2016) .…”

“…Together, these results suggest that underlying geneSc differences among the mouse strains influence the Sme and type of cancer development irrespecSve of the iniSaSng mutaSon (Branca et al, 2020).…”

“…However, Trp53-deficient strains show not only a remarkable difference in cancer onset, but also in tumor-type spectrum; 129S/J Trp53-/and C57BL6/J Trp53-/mice develop primarily thymic lymphomas, whereas BALB/cJ Trp53-/mice develop mammary tumors and SJL/J Trp53-/mice develop tesScular teratomas in addiSon to thymic lymphomas (Branca et al, 2020;Donehower et al, 1992;Jacks et al, 1994;Kuperwasser et al, 2000;Olive et al, 2004).…”

“…One would predict that a null mutation that completely removes the Trp53 protein (p53 in human) —a critical tumor suppressor and apoptosis regulator—would not be influenced by the strain background, since cell-cycle and apoptosis genes are conserved among mouse strains (Lozano and Levine, 2016). However, Trp53-deficient strains show not only a remarkable difference in cancer onset, but also in tumor-type spectrum; 129S/J Trp53-/- and C57BL6/J Trp53-/- mice develop primarily thymic lymphomas, whereas BALB/cJ Trp53-/- mice develop mammary tumors and SJL/J Trp53- /- mice develop testicular teratomas in addition to thymic lymphomas (Branca et al, 2020; Donehower et al, 1992; Jacks et al, 1994; Kuperwasser et al, 2000; Olive et al, 2004). Together, these results suggest that underlying genetic differences among the mouse strains influence the time and type of cancer development irrespective of the initiating mutation (Branca et al, 2020).…”

Identification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis

“…Of note, the master regulators found in CD4 + T cells in this study are not necessarily involved exclusively in gut inflammation. Some of these master regulators might be related to many other processes, especially those that were not differentially expressed, including Trp53 and Ar1 , which are known to be cell cycle master regulators 35 , 36 . Another limitation is that this study was conducted only with females since male mice behave highly aggressive when housed in groups 37 .…”