No Requirement for V(D)J Recombination in p53-Deficient Thymic Lymphoma

Abstract

The p53 tumor suppressor is activated in response to a variety of cellular stress signals, including DNA damage. Its ability to facilitate growth arrest and/or cell death in response to such signals is believed to be the basis for its tumor suppressor function (see references 5, 16, 22, and 27 for reviews). However, specific in vivo signals that trigger tumor suppression have not been identified. Sixty to eighty percent of the spontaneous malignancies in p53-deficient mice are thymic lymphomas (13, 17), indicating that natural thymocyte events signal p53 tumor suppression. The favored hypothesis is that flawed T-cell receptor (TCR) gene recombination events signal p53-dependent elimination of damaged cells (15,17,24,28). p53 inactivation would thus facilitate the survival of cells carrying tumorigenic mutations. This hypothesis is consistent with several observations, including that (i) double-strand DNA breaks (DSBs) trigger p53 responses (29), (ii) p53 is required for DNA damage-induced thymocyte apoptosis (11, 23), (iii) thymic lymphomas induced by p53 deficiency are clonal, indicating that additional tumorigenic events are required (38), and (iv) in scid mice, which accumulate V(D)J breaks, lymphoid malignancies are accelerated by p53 deficiency (15, 28). Since V(D)J translocations are frequently associated with oncogene activation in human and mouse lymphoid tumors, it is reasonable to suspect that these events may be involved in tumorigenesis in the absence of p53-mediated surveillance.V(D)J recombination affects TCR and immunoglobulin (Ig) DNA rearrangement in developing T and B cells to generate a variety of antigen receptor specificities. Normally this process occurs during specific stages of T-and B-cell differentiation to yield a single productive rearrangement per cell for each polypeptide component of the receptor. The initiating event in V(D)J recombination, the generation of specific DSBs, requires two recombination activating genes (RAGs), RAG-1 and RAG-2 (9, 31). Mice deficient in either of these genes fail to undergo V(D)J recombination and are immunodeficient due to the lack of mature T and B cells (25,37). Thus, these mice provide an approach for assessing the role of V(D)J recombination in thymomagenesis associated with p53 deficiency. Here we examine the impact of inactivating V(D)J recombination on tumorigenesis by introducing RAG deficiencies and/or rearranged TCR transgenes into mice with a thymocyte p53 deficiency. Additionally, we analyze the chromosomes of p53-deficient thymomas for evidence of TCR translocations and other aberrations. MATERIALS AND METHODSMice. RAG-1 Ϫ/Ϫ (C57BL/6J-sv/129), scid/scid (C57BL/6J), TgN(TcrLCMV) (B6D2), and p53 Ϫ/Ϫ (C57BL/6J) mice were from Jackson Laboratory, and RAG-2 Ϫ/Ϫ mice (129, SvEv) were from Taconic Laboratory. TgT⌬N mice (B6D2), previously referred to as TgLST1135, abundantly express the dl1135 simian virus 40 (SV40) large T antigen (T-Ag) in thymocytes under the regulation of the lymphotropic papovavirus transcriptional signals (38). Although l...

Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells

“…The majority of A N/ϩ p N/N control mice died from T cell lymphomas that lacked clonal translocations (data not shown) and presumably represent the T cell lymphomas that normally arise on a p53-deficient background (12,19,30). In contrast, of two A N/N p N/N thymic lymphomas analyzed by SKY, both had translocations involving chromosome 14, which contains the T cell antigen receptor (TCR)-␣ locus.…”

Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice

“…Therefore, apoptosis cannot account for the prolonged latency of tumorigenesis inTrp53 515C/515C mice. Trp53-null cells or tumors are aneuploid [16][17][18][19] , and we postulated that the genomes of Trp53 515C/515C tumors were more stable owing to their longer latency. Consistent with this hypothesis, eight of eight lymphomas (two of which were T-cell lymphomas) in Trp53 515C/515C mice had either a diploid (six of eight) or tetraploid DNA content (two of eight; Fig.…”

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

“…Despite the role of Tp53 in suppressing B lineage lymphomas with Ig translocations in cell populations experiencing elevated frequencies of RAG/AID-initiated DSB intermediates, Tp53 À/À mice succumb to thymic lymphomas that lack clonal translocations involving Tcr or other genomic loci and do not develop B lymphoid tumors (Liao et al, 1998;Bassing et al, 2003;Celeste et al, 2003a). Mice expressing apoptosis-defective Tp53 mutants in all cells beginning in early embryos develop B lineage lymphomas (MacPherson et al, 2004;Slatter et al, 2009); however, whether these malignancies contain Ig translocations or other types of genomic instability was not reported.…”