Genetic instability is associated with histological transformation of follicle center lymphoma

Nagy, Mónika; Balázs, Margit; Ádám, Zsuzsanna; Petko, Zsolt; Tímár, Botond; Szereday, Z; László, Terézia; Warnke, Roger A.; Matolcsy, András

doi:10.1038/sj.leu.2401978

Cited by 44 publications

(29 citation statements)

References 42 publications

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“…12,16,24 Karyotypic analysis has also shown that transformed DLBCL are cytogenetically more unstable, resulting in a scattered picture of numerical alterations. 17 In close agreement with previous studies, 5,12,13 the most common alterations in our series of transformed DLBCL were þ Xq21-26 (36%), þ 7pter-q22 (25%), þ 12q15 (29%), and þ 18q21 (21%), as well as À6q16-21 (25%), À8p22-pter (18%), and À17p (18%).…”

Section: Discussionmentioning

confidence: 99%

Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma

et al. 2007

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Follicular lymphoma is commonly transformed to a more aggressive diffuse large B-cell lymphoma (DLBCL). In order to molecularely characterize this histiological and clinical transformation, comparative genomic hybridization was applied on 23 follicular lymphoma and 35 transformed DLBCL tumors from a total of 30 patients. The results were also compared with our published findings in de novo DLBCL. Copy number changes were detected in 70% of follicular lymphoma and in 97% of transformed DLBCL. In follicular lymphoma, the most common alterations were þ 18q21 (33%), þ Xq25-26 (28%), þ 1q31-32 (23%), and À17p (23%), whereas transformed DLBCL most frequently exhibited þ Xq25-26 (36%), þ 12q15 (29%), þ 7pter-q22 (25%), þ 8q21 (21%), and À6q16-21(25%). Transformed DLBCL showed significantly more alterations as compared to follicular lymphoma (P ¼ 0.0001), and the alterations À6q16-21 and þ 7pter-q22 were only found in transformed DLBCL but not in follicular lymphoma (P ¼ 0.02). Alterations involving þ 13q22 were significantly less frequent, whereas À4q13-21 was more common in transformed as compared to de novo DLBCL (P ¼ 0.01 and P ¼ 0.02, respectively). Clinical progression from follicular lymphoma to transformed DLBCL is on the genetic level associated with acquirement of increasing number of genomic copy number changes, with non-random involvement of specific target regions. The findings support diverse genetic background between transformed and de novo DLBCL.

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Section: Discussionmentioning

confidence: 99%

Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma

et al. 2007

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“…The median age at transformation was 52 (range 27-73) years. Presentation lymph nodes were analysed in 10/26 patients ( Patients 6,7,9,12,17,19,[20][21][22][23][24][25]. The t(14;18)(q32;q21) cell lines DoHH2, RL2261 and SCI-1 were also included for analysis.…”

Section: Tissue Samplesmentioning

confidence: 99%

“…Comparative genomic hybridization (CGH) analysis of sequential FL and t-FL biopsy samples has been used to determine the critical copy number changes in these tumours. [10][11][12][13] More recently, arraybased high-density genotype analysis has become available. The application of this approach to other malignancies has not only revealed copy number changes but has also uncovered the presence of large regions of homozygosity in the absence of copy number change.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

et al. 2007

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Single-nucleotide polymorphism (SNP) array analysis was performed using the 10K GeneChip array on a series of 26 paired follicular lymphoma (FL) and transformed-FL (t-FL) biopsies and the lymphoma cell lines SCI-1, DoHH2 and RL2261. Regions of acquired homozygosity were detected in 43/52 (83%) primary specimens with a mean of 1.7 and 3.0 aberrations in the FL and t-FL, respectively. A notable feature was the occurrence of recurring sites of acquired uniparental disomy (aUDP) on 6p, 9p, 12q and 17p in cell lines and primary samples. Homozygosity of 9p and 17p arose predominantly in t-FL and in three cases rendered the cell homozygous for a preexisting mutation of either CDKN2A or TP53. These data suggest that mutation precedes mitotic recombination, which leads to the removal of the remaining wild-type allele. In all, 18 cases exhibited abnormalities in both FL and t-FL samples. In 10 cases blocks of homozygosity were detected in FL that were absent in the subsequent t-FL sample. These differences support the notion that FL and t-FL may arise in a proportion of patients by divergence from a common malignant ancestor cell rather than by clonal evolution from an antecedent FL.

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“…Second, a retroviral insertion upstream of c-rel has been found in one chicken B-cell lymphoma (Kabrun et al, 1990). Third, the human REL gene is frequently amplified in human B-cell lymphomas, including Hodgkin's lymphomas (Joos et al, 2002;Martı´n-Subero et al, 2002), diffuse large-cell B-cell lymphomas (Lu et al, 1991;Houldsworth et al, 1996;Joos et al, 1996;Barth et al, 1998Barth et al, , 2001Rao et al, 1998;Palanisamy et al, 2002;Rosenwald et al, 2002), and follicular lymphomas (Goff et al, 2000;Nagy et al, 2000;Neat et al, 2001). Fourth, the REL locus has undergone genetic alterations in one diffuse large B-cell lymphoma cell line Lu et al, 1991) and one primary Hodgkin's lymphoma (Barth et al, 2003), which result in the production of C-terminally truncated REL proteins.…”

Section: Introductionmentioning

confidence: 99%

Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human transcription factor REL in chicken spleen cells

2003

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The REL gene is amplified in many human B-cell lymphomas and we have previously shown that expression of REL from a retroviral vector can malignantly transform chicken spleen cells in vitro. To identify REL protein functions necessary for malignant transformation, we have performed deletion analysis on REL sequences encoding residues of two C-terminal subdomains that are involved in transcriptional activation. We find that deletion of both Cterminal transactivation subdomains abolishes the ability of REL to transform chicken spleen cells in vitro. In contrast, deletion of either transactivation subdomain alone, which reduces the transactivation ability of REL, enhances the transforming activity of REL. Transforming REL mutants missing C-terminal sequences can also be selected at a low frequency in vitro. The REL transactivation domain can be functionally replaced in transformation assays by a portion of the VP16 transactivation domain that activates at a level similar to RELtransforming mutants. We also find that deletion of 29 C-terminal amino acids causes the subcellular localization of REL to change from cytoplasmic to nuclear in chicken embryo fibroblasts. In contrast, wild-type REL and all transforming REL mutants are located primarily in the cytoplasm of transformed spleen cells. Nevertheless, treatment of transformed spleen cells with leptomycin B causes wild-type REL and two REL mutants to relocalize to the nucleus, and nuclear extracts from these transformed cells contain REL DNA-binding activity. Taken together, these results suggest the following: (1) that REL must activate transcription to transform cells in vitro; (2) that a reduced level of transactivation enhances the oncogenicity of REL; (3) that REL shuttles from the cytoplasm to the nucleus in transformed chicken spleen cells; and (4) that mutations in REL, in addition to amplifications, could activate its oncogenicity in human lymphomas.

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Genetic instability is associated with histological transformation of follicle center lymphoma

Cited by 44 publications

References 42 publications

Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma

Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human transcription factor REL in chicken spleen cells

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