Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2

Abstract

IntroductionHodgkin lymphoma (HL), which accounts for approximately one third of all malignant lymphomas, is characterized by the presence of only a small fraction of malignant cells. Neoplastic cells represented as mononucleated Hodgkin-and multinucleated Reed-Sternberg cells (HRS cells) are embedded in a varying infiltrate of reactive cells including B and T lymphocytes, eosinophils, plasma cells, and fibroblasts. 1 According to the new World Health Organization (WHO) classification, 2 4 well-defined histotypes of classical Hodgkin lymphoma (cHL) can be distinguished: lymphocyte-rich (cHL-LR), nodularsclerosis (cHL-NS), mixed-cellularity (cHL-MC), and lymphocytedepletion (cHL-LD). Paragranuloma (nodular lymphocyte predominant Hodgkin lymphoma [NLPHL]) has been shown to be clinically and immunophenotypically distinct and eventually to transform to large B-cell non-Hodgkin lymphoma. This indicates that NLPHL is essentially different from the cHL subtypes.Because of the small number of malignant cells, cytogenetic analysis is particularly difficult in HL and, to date, has not revealed any specific chromosomal rearrangements. Detailed analysis by chromosome banding is further limited by the low mitotic index of neoplastic cells, frequently poor chromosome morphology, and complex karyotypic rearrangements. For these reasons, it is difficult to obtain sufficient numbers of karyotypes for evaluation that are representative of the malignant cell population. 3,4 Alternatively, combined immunohistochemical and cytogenetic analyses by fluorescence in situ hybridization (FISH) have been applied. It could be demonstrated that chromosomal changes are almost exclusively restricted to CD30 ϩ HRS cells. Furthermore, significant heterogeneity in terms of the copy number of single chromosomes was detected using this approach. [5][6][7][8] Recently, comparative genomic hybridization (CGH) was applied in combination with universal polymerase chain reaction (PCR) technology for cytogenetic analyses of HRS cells. 9-11 These analyses indicated higher rates of numerical aberrations of individual chromosomes than had previously been found by banding analysis, in which the identification of numerical changes is difficult because of the complex karyotypes of HRS cells. Gains and losses in more than 50% of the cHL tumors were identified on chromosomal arms 2p, 7q, and 16q, 9,10 whereas in NLPHL, chromosomal arms 1q, 3p, 5q, and Xq were affected. 11 Although the number of analyses is still low (20 cHLs and 20 NLPHLs to date), CGH has already allowed the identification of several imbalanced chromosomal subregions, indicating the localization of candidate genes that may be involved in the etiology of this disease.To further define critical subregions in cHL, a series of 41 tumors was analyzed (a small subset of cases was reported recently 10 ). To this end, collected pools of approximately 30 malignant HRS cells from single tumors were isolated using microdissection technology. Genomic DNA from the individual cell pools was subsequently ampl...

Targeting NF-κB in hematologic malignancies

“…As an alternative or additional mechanism of NF-kB activation, amplifications of the NF-kB/REL gene have been detected by fluorescence in situ hybridization (FISH) of the 2p13-16 locus in HL. 19 In line with the probable relevance of NF-kB for HL pathogenesis, the antiapoptotic NF-kB target gene c-FLIP is constitutively expressed by HRS cells. The presence of c-FLIP may indeed inhibit transmission of proapoptotic signals via death receptors including CD95/Fas/Apo1, as suggested in a study of 59 HL patients.…”

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

“…It is noteworthy that a gain in chromosome 2p has been identified as a recurrent alteration in 20% of patients DLBCL 12,[31][32][33][34][35][36][37] and is the most frequent CGH alteration in classic Hodgkin lymphoma (identified in 50% of patients). 38,39 The common recurrent region expands 4.2 Mb in 2p15-16. 38,39 By using array-CGH, we were able to restrict the minimal common region to 700 Kb in length.…”

“…38,39 The common recurrent region expands 4.2 Mb in 2p15-16. 38,39 By using array-CGH, we were able to restrict the minimal common region to 700 Kb in length. Two oncogenes involved in lymphomagenesis, REL and BCL11A, are located in this region.…”

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

“…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.…”