Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation

Ohi, Hiroyuki; Mishima, Yukio; Kamimura, Kenya; Maruyama, Masaki; Sasai, Ken; Kominami, Ryo

doi:10.1038/sj.onc.1210325

Cited by 29 publications

(34 citation statements)

References 52 publications

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“…Bcl11b and Pten, for example, are also altered in early preleukemic cells and in TLs after irradiation, suggesting that they may be key factors of lymphomagenesis. 46 Importantly, Ikaros and Notch1 intersect in the regulation of normal T-cell development. Additionally, leukemogenesis induced by Ikaros deficiency is similar in phenotype to that induced by constitutively active Notch1.…”

Section: Discussionmentioning

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

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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...

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Section: Discussionmentioning

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

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“…To determine D-J rearrangement patterns in the TCRb locus, polymerase chain reaction (PCR) was performed as described. (24,25) Of allelic loss analysis at the Bcl11b locus, D12Mit53 and D12Mit279 markers were used for PCR as described previously. (7) The PCR reaction was processed through 32 cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 1 min in most cases.…”

Section: Methodsmentioning

confidence: 99%

“…(24) Our previous studies demonstrated that such identical rearrangements were also found in c-ray induced mouse atrophic thymuses, indicating the existence of clonally expanded thymocytes. (24,25) A significant percentage of those thymuses exhibited allelic loss of Bcl11b. These findings raise the question of how and at which stage does the Bcl11b heterozygous genotype contributes to lymphoma development.…”

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confidence: 99%

“…(13,14) Identical rearrangements of the TCRb locus are seen in thymic lymphomas and this establishes clonality of the lymphomas. (24) Our previous studies demonstrated that such identical rearrangements were also found in c-ray induced mouse atrophic thymuses, indicating the existence of clonally expanded thymocytes. (24,25) A significant percentage of those thymuses exhibited allelic loss of Bcl11b.…”

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Bcl11b heterozygosity promotes clonal expansion and differentiation arrest of thymocytes in γ‐irradiated mice

Go¹,

Hirose²,

Morita³

et al. 2010

Cancer Science

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Bcl11b encodes a zinc-finger transcription factor and functions as a haploinsufficient tumor suppressor gene. Bcl11bKO ⁄ KO mice exhibit differentiation arrest of thymocytes during b-selection as has been observed with other mouse models involving knockouts of genes in the Wnt ⁄ b-catenin signaling pathway. Recurrent chromosomal rearrangement at the BCL11B locus occurs in human T-cell leukemias, but it is not clear how such rearrangement would contribute to lymphomagenesis. To address this issue, we studied clonal cell growth, cell number, and differentiation of thymocytes in Bcl11b KO ⁄ + mice at different time points following c-irradiation. Analysis of D-J rearrangement at the T cell receptor b-chain (TCRb) locus and cell surface markers by flow cytometry revealed two distinct populations of clonally growing thymocytes. In one population, thymocytes share a common D-J rearrangement but retain the capacity to differentiate. In contrast, thymocytes in the second population have lost their ability to differentiate. Since the capacity to self renew and differentiate into multiple cell lineages are fundamental properties of adult stem cells, the differentiation competent population of thymocytes that we have isolated could potentially function as cancer stem cells. We also demonstrate increased expression of b-catenin, a well-known oncogenic protein, in Bcl11b KO ⁄ + thymocytes. Collectively, the Bcl11b KO ⁄ + genotype contributes to clonal expansion and differentiation arrest in part through an increase in the level of b-catenin. (Cancer Sci 2010; 101: 1347-1353 C ancer development is a complex, multistep process involving the acquisition of capabilities of cell autonomous proliferation and resistance to apoptosis.(1) This could be a consequence of a sequence of 4-6 mutations that are associated with different stages of the tumor progression.(2) Leukemia and lymphoma are malignancies of hematopoietic cells, and chronic myelogenous leukemia (CML) is among the malignancies characterized with frequently having the bcr ⁄ abl chimeric gene.(3) A two-step process is seen from CML to a subset of acute lymphoblastic leukemia (ALL) bearing bcr ⁄ abl, an aggressive blast crisis phase. (3)(4)(5) This transition requires an arrest of differentiation. Interestingly, CML already possesses intrinsic self-renewal capability like adult tissue stem cells and differentiate to mature, nontumorigenic blood cells. (6) Bcl11b is a haploinsufficient tumor suppressor gene that was isolated from analyses of c-ray induced mouse thymic lymphomas.(7-9) Bcl11b KO ⁄ + mice are susceptible to the development of thymic lymphomas, (9) suggesting that loss or decrease of Bcl11b function contributes to lymphomagenesis. Recurrent chromosomal rearrangement at the human BCL11B locus has been reported in T-cell leukemias, (10)(11)(12) but the effects of the rearrangement are not clear. Bcl11b encodes a zinc-finger transcription factor that is expressed in thymocytes, neurons and other tissues.(13-17) Bcl11b KO ⁄ KO and Bcl11b lox ⁄ lox mice show diffe...

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“…Numerous chromosomal imbalances have been documented in human lymphomas (Hallermann et al, 2004 Ohi et al (2007) in mice with thymic lymphomas after γ-irradiation In this paper the potential DNA changes in two protooncogenes (N-RAS and c-KIT), and TP53 tumour suppressor gene were analyzed in canine lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Canine lymphomas: DNA changes in tumour genes

Drážovská¹,

Šiviková²,

Bona³

2016

Acta fytotechn zootechn

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Lymphoma is the most frequent hematopoietic neoplasm in dog, and it shares some clinical, cytological, histopathological and molecular similarities with humans. In our study, DNA changes in TP53, c-KIT and N-RAS were detected in lymphoma tissues of cross breed bitch and Bernese Mountain Dog bitch. One transition A/G at nucleotide position 138 in exon 5 in TP53 gene and one transition G/A at nucleotide position 35 in exon 8 of c-KIT gene were observed in donor 2. It seems that these genes did not play a key role in canine lymphoma formation and progression.

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Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation

Cited by 29 publications

References 52 publications

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

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

Bcl11b heterozygosity promotes clonal expansion and differentiation arrest of thymocytes in γ‐irradiated mice

Canine lymphomas: DNA changes in tumour genes

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