Lymphoma development in mice and humans: diversity of initiation is followed by convergent cytogenetic evolution.

Klein, George

doi:10.1073/pnas.76.5.2442

Cited by 261 publications

(77 citation statements)

References 74 publications

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“…Note that such effects cannot be detected in bacterial assays. It has been shown repeatedly that clastogenic and aneugenic effects in somatic cells are associated with the development of cancer [32][33][34][35] and a number of earlier studies have shown that the MN assay with exfoliated cells is an appropriate tool to monitor cancer risks in humans caused by exposure to environmental factors or inherited genomic instability. 10,14,16 -18 Therefore, the present findings suggest that khat chewing may cause cancer in the oral cavity or other parts of the upper digestive tract.…”

Section: Discussionmentioning

confidence: 99%

Khat (Catha edulis) consumption causes genotoxic effects in humans

Kassie

Darroudi

Kundi³

et al. 2001

Int. J. Cancer

123

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We used the micronucleus (MN) test to determine the genetic damage caused by khat, a widely consumed psychostimulant plant, in exfoliated cells of volunteers who chewed the drug on a regular basis. In the first study in which we compared the frequency of MN in buccal and bladder mucosa cells in 20 khat consumers (10 -160 g/day) and 10 controls, a pronounced (8-fold) increase in micronucleated buccal mucosa cells was seen among khat consumers; khat consumption did not lead to a detectable elevation of micronucleated bladder mucosa cells. Among heavy khat chewers, 81% of the MN had a centromere signal indicating that khat is aneuploidogenic. To investigate the effect of simultaneous consumption of tobacco and alcoholic beverages, we compared the MN frequency in buccal cells of 25 khat consumers (20 -85 g/day) who smoked cigarettes (15-60/day) and drank alcoholic beverages (15-80 g of pure ethanol/day) with a control group (control group I) of 25 individuals matched for age, body weight, tobacco and alcohol consumption and with another control group of 25 individuals (control group II) not consuming any of the drugs. The frequency of buccal mucosa cells with MN was higher in control group I than in group II and the effect of khat, tobacco and alcohol was found to be additive. A time-kinetics study on khat-induced MN showed that the highest frequency of MN was observed during the fourth week after consumption. In light of the large body of evidence on the close association between genetic damage and cancer, these results suggest that khat consumption, especially when accompanied by alcohol and tobacco consumption, might be a potential cause of oral malignancy. © 2001 Wiley-Liss, Inc. Key words: khat; buccal mucosa; micronuclei; aneugenThe habit of khat chewing has prevailed for centuries among populations in the horn of Africa and the Arabian peninsula. The leaves of Catha edulis (commonly termed as q'at or khat) contain the natural amphetamine cathinone, which has euphoric and psychostimulant effects. 1,2 Due to its widespread consumption, the production of khat has become an important economic factor. Apart from coffee, khat is the largest cash crop in Yemen and Ethiopia. 3 It has been estimated that in Somalia and Yemen up to one-third of the family income is spent on chewing khat 2 and about 80% of the adult population of these countries are consumers of khat. In Yemen, approximately US$700 million are spent on khat, and in Somalia the annual expenditure for the khat import is about US$57 million.Toxic effects of khat in humans have been studied over the last 20 years and include multiple symptoms such as euphoria, anorexia, insomnia, gastritis, hypertension and impotence. 4 In bacteria, crude khat extract caused gene mutations and cathinone and crude khat extract induced structural chromosomal aberrations 5 and MN formation 6 in bone marrow cells of mice. However, no data on the potential genotoxic effects of khat in humans are available. It is well established that genotoxic effects lead to induction of cancer...

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Section: Discussionmentioning

confidence: 99%

Khat (Catha edulis) consumption causes genotoxic effects in humans

Kassie

Darroudi

Kundi³

et al. 2001

Int. J. Cancer

123

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“…Genetic changes of these two genes were also found in human hematopoietic malignancies (Sun et al, 1999;Bernard et al, 2001;Itoyama et al, 2001;Yagi et al, 2002;MacLeod et al, 2003;Nagel et al, 2003;Bezrookove and van Zelderen-Bhola, 2004;Przybylski et al, 2005). Studies in other laboratories implicated several genes in the lymphoma development such as Myc, Notch1 and PTEN (Klein, 1979;Graham et al, 1985;Ellisen et al, 1991;Mao et al, 2003;Lin et al, 2006;O'Neil et al, 2006). On the other hand, mutation frequencies of mostly delineated ras and p53 genes were low in radiogenic thymic lymphomas Brathwaite et al, 1992).…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2007

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Whole-body c-irradiation to mice causes thymic atrophy where a population of precancerous cells with mutation can be found. Thus, clonal growth and DNA changes at Bcl11b, Ikaros, Pten, Notch1 and Myc were examined in not only thymic lymphomas but also in atrophic thymuses at various times after irradiation. Clonal expansion was detected from the distinct patterns of rearrangements at the TCRb receptor locus in a fraction of atrophic thymuses at as early as 30 days after irradiation. This expansion may be in part owing to the rearranged TCRb signaling because the transfer of bone marrow cells with the rearrangement and the wild-type locus into severecombined immunodeficiency mice showed preferential growth of the rearranged thymocytes in atrophic thymus. Loss of heterozygosity (LOH) at Bcl11b and trisomy of Myc were found at high frequencies in both lymphomas and atrophic thymuses, and in contrast, LOH at Ikaros and Pten were rare in atrophic thymuses but prevalent in lymphomas. Notch1 activation was detected in lymphomas and in atrophic thymuses only at a late stage. Similar patterns of DNA changes were found in atrophic thymuses induced in Bcl11b þ /À mice. These results suggest the order of genetic changes during lymphomagenesis, Bcl11b and Myc being at the early stage; whereas Ikaros, Pten and Notch1 at the late stage.

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“…In addition to immortalization of B lymphocytes, oncogenesis by EBV in Burkitt's lymphoma requires chromosomal transformation [2]. Hanto et al [6] describe the karyotypes of six lymphomas.…”

Section: Discussionmentioning

confidence: 99%

“…The precise role of the virus in carcinogenesis is unclear, although in Burkitt's lymphoma the importance of viral transformation of infected B lymphocytes and chromosomal translocations has been emphasized [2]. It is even less clear in lymphomas and lymphoproliferative lesions arising in immuno-compromised patients, where the immunopathology may not be uniform and where chromosomal studies are largely lacking.…”

Section: Introductionmentioning

confidence: 96%

Epstein-Barr Virus Infections and DNA Hybridization Studies in Posttransplantation Lymphoma and Lymphoproliferative Lesions: The Role of Primary Infection

Ho¹,

Miller²,

Atchison³

et al. 1985

Journal of Infectious Diseases

431

161

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Fourteen patients who developed B cell lymphomas or lymphoproliferative lesions after kidney, liver, heart, or heart-lung transplantation in Pittsburgh during [1981][1982][1983] had active infection with Epstein-Barr virus (EBV) of the primary (six patients), reactivated (seven patients), or chronic (one patient) type. In transplant patients without tumors, the incidence of EBV infection was 30% (39 of 128). Only three of these patients had primary infections. Thus the frequency of active infection was significantly higher in patients with tumors, and patients with primary infections were at greater risk of developing tumors. Five of 13 tumors tested contained EBV nuclear antigen (EBNA) and nine of 11 contained EBV genomes detected by DNA-DNA hybridization with BamHI K, BamHI W, or EcoRI B cloned probes. All EBNA-positive tumors, except one, were also positive by hybridization. Only one tumor was negative for both EBNA and EBV DNA. These data suggest that EBV plays an etiologic role in the development of these lesions.Epstein-Barr virus (EBV) is a human herpesvirus associated with an array of conditions that range from inapparent infection and infectious mononucleosis to lethal lymphoproliferative syndromes, nasopharyngeal carcinoma, Burkitt's lymphoma, and B cell lymphomas in immunocompromised patients [1]. The precise role of the virus in carcinogenesis is unclear, although in Burkitt's lymphoma the importance of viral transformation of infected B lymphocytes and chromosomal translocations has been emphasized [2]. It is even less clear in lymphomas and lymphoproliferative lesions arising in immuno-compromised patients, where the immunopathology may not be uniform and where chromosomal studies are largely lacking.Recently, we reported on the reversibility of lymphomas and lymphoproliferative lesions in a series of 17 transplant patients after reduction of cyclosporine and steroid immunosuppression [3]. In that preliminary report we noted that seven of these patients had evidence of primary EBV infections and eight had evidence of reactivated infection. Six tumors had evidence of EBV nuclear antigen (EBNA) and seven had evidence of EBV DNA by nucleic acid hybridization. [6] reported the results of studies on 19 renal transplant patients who developed lymphoproliferative disorders and lymphomas after transplantation. All the patients except one were receiving azathioprine, prednisone, and antithymocyte globulin. Two of their patients developed primary EBV infection, in six the infection reactivated, and 12 had evidence of EBV DNA in their tumors by hybridization studies. Bieber et al. [7] reported that five of 39 heart transplant recipients receiving cyclosporine, prednisone, and antithymocyte globulin developed lymphomas. Four tumors were positive for EBV DNA by cRNA-DNA filter hybridization, and three patients had serological evidence of EBV infection.We report here evidence for active EBV infection in all of our patients with tumors and a significantly higher frequency of primary infection than found i...

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Lymphoma development in mice and humans: diversity of initiation is followed by convergent cytogenetic evolution.

Cited by 261 publications

References 74 publications

Khat (Catha edulis) consumption causes genotoxic effects in humans

Khat (Catha edulis) consumption causes genotoxic effects in humans

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

Epstein-Barr Virus Infections and DNA Hybridization Studies in Posttransplantation Lymphoma and Lymphoproliferative Lesions: The Role of Primary Infection

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