The significance of <i>TP53</i> in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target

Cheung, Katherine; Horsman, Douglas E.; Gascoyne, Randy D.

doi:10.1111/j.1365-2141.2009.07739.x

Cited by 55 publications

(53 citation statements)

References 112 publications

(160 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These malignancies frequently contain oncogenic IG translocations. Inactivating somatic mutations of TP53 correlate with IGH translocations in diffuse large B-cell lymphoma (DLBCL) and BL, as well as chemotherapy resistance, rapid disease progression and poor prognosis in patients with B lymphoid tumors (Kuppers, 2005;Cheung et al, 2009). Our analysis of mb1-cre:Tp53 flox/flox mice provides evidence that the somatic TP53 mutations found in DLBCL and BL may contribute to the development of these malignancies.…”

Section: Resultsmentioning

confidence: 75%

“…Upon G1 phase DSBs, TP53 functions to prevent G1/S transition until DNA breaks are repaired or trigger apoptosis if the damage is un-repairable (Vousden and Prives, 2009). Somatic inactivation of TP53 is observed in human tumors containing genomic instability including B lineage lymphomas with clonal IG translocations generated through aberrant V(D)J recombination or CSR (Cheung et al, 2009), indicating that TP53 may prevent genomic instability such as RAG/AID-initiated translocations from forming and/or driving transformation. Multiple independent observations in mice support these notions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2011

View full text Add to dashboard Cite

Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53 À/À ) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multilineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53 flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre: Tp53 flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs.Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.

show abstract

Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…3 However, the TP53 gene, which is an essential gene for genomic integrity, has not been extensively studied in MCL, although TP53 mutations have been reported more frequently in the clinically aggressive blastoid variant. 1 In one of the larger reports from the Leukemia and Lymphoma Molecular Profiling Project (LLMPP), TP53 mutations were found in 16/82 (20%) of MCL samples and were associated with an unfavorable clinical course. 4 That notwithstanding, the prognostic relevance of 17p deletions (which include the TP53 gene) in MCL is less clear, although several studies have indicated an association with short survival.…”

mentioning

confidence: 99%

“…1 Nevertheless, TP53 mutations have been reported to be associated with poor prognosis in hematological malignancies, such as diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). 1 Furthermore, the profile of TP53 mutations appears to vary between different cancers, and a relationship has been found between certain carcinogens and specific mutation types. 2 Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma characterized by the t(11;14)(q13;q32), leading to cyclin D1 overexpression.…”

mentioning

confidence: 99%

Impact of TP53 mutation and 17p deletion in mantle cell lymphoma

et al. 2011

View full text Add to dashboard Cite

“…19 Studies using the mutant Kras G12D mouse model implicate hyperactive Ras in TL pathogenesis. 20 Elevated levels of Ras signaling have been observed in $50% of patients with T-ALL.…”

mentioning

confidence: 99%

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

Hirano

Kakinuma

Amasaki³

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

Cancer risk associated with radiation exposure is considered the result of concurrent exposure to other natural and manmade carcinogens. Available data on the molecular characteristics of cancer after simultaneous exposure to radiation and chemicals are insufficient. In our study, we used a mouse thymic lymphoma (TL) model that was synergistically induced by simultaneous exposure to X-rays and N-ethyl-N-nitrosourea (ENU) at subcarcinogenic doses and analyzed the mutation frequency and spectrum of the TL-associated genes Ikaros, Notch1, p53 and Kras. We found that the point mutation frequency in Ikaros was significantly increased to 47% for simultaneous exposure compared to 13 and 0% for X-ray and ENU exposure alone, respectively. These mutations were mostly G:C > A:T at non-CpG sites and T:A > C:G, both of which are characteristic of ENU mutagenesis. About half of the point mutations were accompanied by loss of heterozygosity (LOH), typical of X-irradiation. The remaining half did not include LOH, which suggests that they were dominant-negative mutations. In Notch1, the frequency of abnormalities was high (>58%) regardless of the treatment, suggesting that Notch1 aberration may be important for T-cell lymphomagenesis. The p53 and Kras mutation frequencies were low for all treatments (<23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both Ikaros and Notch1, increased after simultaneous exposure. Thus, after simultaneous exposure, Ikaros is a critical target and is inactivated by ENU-induced point mutations and/or X-ray-induced LOH in T-cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor-associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.A multitude of natural and manmade chemicals with cancerinitiating and cancer-promoting potential are present in the environment. Many human cancers show considerable dependence on lifestyle, such as the use of tobacco, and dietary factors. 1 Moreover, radiation carcinogenesis in humans is considered to result from the combined effect of radiation exposure and environmental carcinogens. There have been many attempts to estimate the risk of such combined exposure in animal and cell culture models. 2,3 There is, however, almost no information about the molecular mechanism that leads to carcinogenesis following combined exposure. Murine thymic lymphoma (TL) can be reproducibly induced by exposure to ionizing radiation and chemical carcinogens such as N-ethyl-N-nitrosourea (ENU), and this model is considered useful in the search for and Key words: simultaneous exposure, X-ray, N-ethyl-N-nitrosourea, thymic lymphoma, Ikaros Abbreviations: B-ALL: B-cell acute lymphoblastic leukemia; ENU: N-ethyl-N-nitrosourea; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gpt: guanine phosphoribosyltransferase; HD: heterodimerization; Hes1: hairy enhancer of split-1; LOH: loss of heterozygosity; Mgmt: O 6 -methylguanine-DNA methyltransferase; PEST: polypeptide rich in proline, glutamate, serine and...

show abstract

The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target

Cited by 55 publications

References 112 publications

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

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

Impact of TP53 mutation and 17p deletion in mantle cell lymphoma

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

Contact Info

Product

Resources

About