title: Somatic inactivation of Tp53 in hematopoietic stem cells or thymocytes predisposes mice to thymic lymphomas with clonal translocations.
abstract: TP53 protects cells from transformation by responding to stresses including aneuploidy and DNA double-strand breaks (DSBs). TP53 induces apoptosis of lymphocytes with persistent DSBs at antigen receptor loci and other genomic loci to prevent these lesions from generating oncogenic translocations. Despite this critical function of TP53, germline Tp53(-/-) mice succumb to immature T-cell (thymic) lymphomas that exhibit aneuploidy and lack clonal translocations. However, Tp53(-/-) mice occasionally develop B lineage lymphomas and Tp53 deletion in pro-B cells causes lymphomas with oncogenic immunoglobulin (Ig) locus translocations. In addition, human lymphoid cancers with somatic TP53 inactivation often harbor oncogenic IG or T-cell receptor (TCR) locus translocations. To determine whether somatic Tp53 inactivation unmasks translocations or alters the frequency of B lineage tumors in mice, we generated and analyzed mice with conditional Tp53 deletion initiating in hematopoietic stem cells (HSCs) or in lineage-committed thymocytes. Median tumor-free survival of each strain was similar to the lifespan of Tp53(-/-) mice. Mice with HSC deletion of Tp53 predominantly succumbed to thymic lymphomas with clonal translocations not involving Tcr loci; however, these mice occasionally developed mature B-cell lymphomas that harbored clonal Ig translocations. Deletion of Tp53 in thymocytes caused thymic lymphomas with aneuploidy and/or clonal translocations, including oncogenic Tcr locus translocations. Our data demonstrate that the developmental stage of Tp53 inactivation affects karyotypes of lymphoid malignancies in mice where somatic deletion of Tp53 initiating in thymocytes is sufficient to cause thymic lymphomas with oncogenic translocations.
authors.affiliation: Cell and Molecular Biology Graduate Group; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA; Division of Cancer Pathobiology; Department of Pathology and Laboratory Medicine; Center for Childhood Cancer Research; Children's Hospital of Philadelphia Research Institute; Philadelphia, PA USA; Abramson Family Cancer Research Institute; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Amy
authors.initials: A
authors.lastname: DeMicco
authors.forename: Katherine
authors.initials: K
authors.lastname: Yang-Iott
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002999:Clone Cells; D017353:Gene Deletion; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D060168:Thymocytes / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: Tp53; thymic lymphoma; translocations
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