title: Immune deficiency augments the prevalence of p53 loss of heterozygosity in spontaneous tumors but not bi-directional loss of heterozygosity in bone marrow progenitors.
abstract: p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li-Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo. Surprisingly, the loss of either the wild-type p53 allele or mutant p53 allele was detected with a three-to-one ratio in favor of losing the mutant allele. In this study, we examined whether the immune-system can affect the LOH directionality in bone marrow progenitors. We found that mesenchymal progenitor cells derived from immune-deficient mice exhibited the same preference of losing the mutant p53 allele as immune-competent matched cells, nevertheless, these animals showed a significantly shorter tumor-free survival, indicating the possible involvement of immune surveillance in this model. Surprisingly, spontaneous tumors of p53 heterozygous immune-deficient mice exhibited a significantly higher incidence of p53 LOH compared to that observed in tumors derived of p53 heterozygous immune-competent mice. These findings indicate that the immune-system may affect the p53 LOH prevalence in spontaneous tumors. Thus suggesting that the immune-system may recognize and clear cells that underwent p53 LOH, whereas in immune-compromised mice, those cells will form tumors with shorter latency. In individuals with a competent immune-system, p53 LOH independent pathways may induce malignant transformation which requires a longer tumor latency. Moreover, this data may imply that the current immunotherapy treatment aimed at abrogating the inhibition of cellular immune checkpoints may be beneficial for LFS patients.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Shetzer
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Napchan
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Tom
authors.initials: T
authors.lastname: Kaufman
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Alina
authors.initials: A
authors.lastname: Molchadsky
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Perry
authors.initials: P
authors.lastname: Tal
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Goldfinger
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
mesh_terms: D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D016158:Genes, p53; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D016867:Immunocompromised Host; D007157:Immunologic Surveillance / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics / Q000276:immunology*; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D019139:Tumor Escape; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D007376:Interleukin-2; D016159:Tumor Suppressor Protein p53; C064658:RAG-1 protein
keywords: immune deficiency; loss of heterozygosity; p53