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(Q32;Q21) Are the Main Chromosomal Abnormalities Involving MLT/MALT1 in MALT Lymphomas

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(Q32;Q21) Are the Main Chromosomal Abnormalities Involving MLT/MALT1 in MALT Lymphomas Leukemia (2003) 17, 2225–2229 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas EM Murga Penas1, K Hinz1,KRo¨ser2, C Copie-Bergman3, I Wlodarska4, P Marynen4, A Hagemeijer4, P Gaulard3,TLo¨ning2, DK Hossfeld1 and J Dierlamm1 1Department of Medicine, Hamburg, Germany; 2Department of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 3Department of Pathology, Centre Hospitalier Universitaire, Henri Mondor, Cre´teil, France; and 4Center for Human Genetics and Flanders Interuniversity, Institute for Biotechnology, University of Leuven, Leuven, Belgium The recently discovered MLT/MALT1 gene is fused with the not respond to Helicobacter pylori eradication therapy and API2 gene in the t(11;18)(q21;q21), which characterizes about H. pylori-negative gastric MALT lymphomas with a rather one-third of MALT lymphomas. In order to screen for variant 15,16 translocations and amplifications of MLT/MALT1, we have aggressive clinical course. developed a novel, undirected two-color interphase fluores- Recently, the t(14;18)(q32;q21) involving the MLT/MALT1 cence in situ hybridization (FISH) assay with two PAC clones and IGH genes has been identified as a new frequent flanking MLT/MALT1. This assay was applied to 108 marginal chromosomal translocation in MALT lymphomas.17,18 The zone B-cell lymphomas (MZBCLs), including 72 extranodal t(14;18) characterizes MALT lymphomas in locations, such as MALT lymphomas, 17 nodal, and 19 splenic MZBCL. In 19 MALT liver, skin, parotid gland, and ocular adnexa that rarely harbor lymphomas (26%), but in none of the nodal or splenic MZBCL, 18 separated hybridization signals of the MLT/MALT1 flanking the t(11;18)(q21;q21). probes, were found. Further FISH analyses showed that 12 of In addition to gene rearrangements by translocations, gene these 19 cases displayed the classical t(11;18) and the amplification represents another mechanism in the pathogenesis remaining seven cases revealed the novel t(14;18)(q32;q21), and disease progression of non-Hodgkin’s lymphomas (NHL). involving the MLT/MALT1 and IGH genes. The frequency at Such amplifications frequently involve the BCL2 gene on which these translocations occurred varied significantly with 18q21.17 However, the incidence of MLT/MALT1 amplifications the primary location of disease. The t(11;18) was mainly detected in gastrointestinal MALT lymphomas, whereas the in NHL, especially MALT lymphomas, is unknown. t(14;18) occurred in MALT lymphomas of the parotid gland and To screen for all kind of translocations and amplifications the conjunctiva. Amplification of MLT/MALT1 was not observed involving the MLT/MALT1 gene, we have developed a novel, in any of the lymphomas analyzed. We conclude that the undirected two-color fluorescence in situ hybridization (FISH) translocations t(11;18)(q21;q21) and t(14;18)(q21;q32) represent assay with two PAC clones flanking the MLT/MALT1 gene. This the main structural aberrations involving MLT/MALT1 in MALT assay was applied to a large series of MZBCL, including 72 lymphomas, whereas true amplifications of MLT/MALT1 occur rarely in MZBCL. extranodal, 17 nodal, and 19 splenic cases. Leukemia (2003) 17, 2225–2229. doi:10.1038/sj.leu.2403122 Published online 21 August 2003 Keywords: MLT/MALT1; MALT lymphoma; FISH; translocations; Materials and methods amplification Patients’ samples Introduction In all, 108 cases of MZBCL were collected based on the availability of fixed cells, frozen, or paraffin-embedded tissue The MLT/MALT1 gene was discovered due to its involvement in from the University Hospital Hamburg-Eppendorf, Hamburg, the translocation t(11;18)(q21;q21) associated with extranodal Germany (n ¼ 60), the Centre Hospitalier Universitaire Henri marginal zone B-cell lymphoma (MZBCL) of the MALT type and ¼ 1–6 Mondor, Cre´teil, France (n 26), and the Center for Human characterizes about one-third of the cases. The Genetics of University of Leuven, Leuven, Belgium (n ¼ 22). The t(11;18)(q21;q21) leads to a fusion of the apoptosis inhibitor 108 MZBCL included 72 extranodal MALT lymphomas from gene API2 on chromosome 11 and the novel MLT/MALT1 gene, 3,7,8 various locations (stomach (n ¼ 31), parotid gland (n ¼ 28), a human paracaspase, on chromosome 18. The pathoge- intestine (n ¼ 5), conjunctiva (n ¼ 3), lung (n ¼ 1), skin (n ¼ 1), netic relevant event involves the derivative chromosome 11 and breast (n ¼ 1), thymus (n ¼ 1), and submaxillary gland (n ¼ 1)), leads to linkage of the three baculovirus IAP repeat (BIR) 17 nodal, and 19 splenic MZBCL. All MALT lymphomas were domains present in the N-terminus of API2 and a variable part of studied at the time of primary diagnosis. All lymphomas were MLT/MALT1, which always contains the caspase p20-like 3,7,9–11 classified according to the WHO classification and showed the domain. The chimeric protein effectively activates typical histological features of MZBCL. NF-kB, a potential prosurvival signal in B cells.12,13 The t(11;18)(q21;q21) has mainly been observed in low- grade MALT lymphomas of the gastrointestinal tract and the Preparation of the specimens lung.2,4–6,14 Recent studies have also shown that the t(11;18) confers important prognostic implications, since this transloca- For the present study, we used freshly prepared cytospin tion has been associated with gastric MALT lymphomas that do preparations of cells isolated by manual disaggregation from frozen tumor tissues (n ¼ 58) and formalin-fixed paraffin- Correspondence: Dr J Dierlamm, Department of Medicine, University embedded tissues (n ¼ 24), or cells that were fixed with Hospital Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany; Fax: þ 49 40 42803 2186 methanol–acetic acid and had been previously cultured Received 27 May 2003; accepted 9 July 2003; Published online 21 (n ¼ 26). The preparation of methanol–acetic acid fixed and August 2003 frozen cells was performed as previously described.5 The Detection of abnormalities involving MLT/MALT1 by FISH EM Murga Penas et al 2226 paraffin-embedded cells were collected by carefully scraping off cosmid Ca1 (hybridizing to the alpha constant region of the paraffin blocks. The scraped material was deparaffinized with IGH locus).19 two 10 min incubations in xylene substitute Rotihistol (Roth, Amplification of MLT/MALT1 was defined as described and Karlsruhe, Germany) and rehydrated in a graded ethanol series validated for the detection of oncogene amplification.20,21 The (100, 90, and 70%, 2 min each). The samples were then criteria included the presence of individual tumor cells with enzymatically digested with a freshly prepared solution contain- tight clusters of MLT/MALT1 interphase FISH signals, with more ing 10 ml of proteinase K (10 mg/ml) (Sigma, Steinheim, than five MLT/MALT1 signals per cell or with two-fold higher Germany) for 30 min at 451C and washed in 1 Â phosphate- number of MLT/MALT1 than D18Z1 (centromere 18) signals. All buffered saline (PBS). Thereafter, the cells were incubated for cases with more or less than two MLT/MALT1-specific signals 30 min in 0.075 mol/l KCl, washed twice in 1 Â PBS, and used were further analyzed with DNA probes hybridizing to the BCL2 for preparation of cytospins. The cytospins were fixed for 10 min gene on 18q21 (YAC yA153A6)22 and the centromeric regions in methanol–acetic acid followed by 5 min incubation in a of chromosomes 18 (D18Z1) and 11 (D11Z1) (both from Oncor, solution containing 1% formaldehyde, 1 Â PBS, and 50 mmol/l Gaithersburg, MD, USA). magnesium dichloride (MgCl2). After a short wash in 1 Â PBS and dehydration in a graded ethanol series, the preparations were subjected to FISH analysis. Fluorescence in situ hybridization DNA labeling with biotin- (PAC 117B5) and digoxigenin-dUTP Probe selection (PAC 59N7) by nick translation and FISH were performed according to standard methods as previously described.5,23 For Dual-color interphase FISH was performed using two differen- the cytospin preparations from frozen tumor tissue, 80 ng of PAC m tially labeled PAC clones flanking the MLT/MALT1 gene (both 59N7, 50 ng of PAC 117B5, and 11 g of Cot-1 DNA, for the obtained from the RPCI-6 library, Roswell Park Cancer Institute, fixed cell preparations, 140 ng of PAC 59N7, 140 ng of PAC m Buffalo, NY, USA). PAC 59N7 contains sequences derived 117B5, and 11 g of Cot-1 DNA, and for the preparations immediately downstream of the MLT/MALT1 gene and is obtained from the paraffin-embedded tumor tissue, 160 ng PAC m translocated to the partner chromosome in case of a transloca- 117B5, 160 ng PAC 59N7, and 14 g Cot-1 DNA were used. 5 m tion involving MLT/MALT1 (Figure 1a). PAC 117B5 contains The probe DNA was dissolved in 5 l of hybridization mixture, sequences derived immediately upstream of MLT/MALT1 and applied to the slide, and covered with a round 13 mm coverslip. remains on chromosome 18 in case of a translocation of MLT/ A total of 200 well-preserved, separately located interphase cells MALT1.5 In normal cells, two fused or colocalized hybridization with clearly visible, distinct signals were analyzed in each case. signals of the two MLT/MALT1 flanking PAC clones can be seen. In case of a translocation with a breakpoint within MLT/MALT1 one of the fusion signals is replaced by separated green and red Determination of cutoff levels signals (Figure 1b). Cases with separated MLT/MALT1 signals were further The cutoff levels for the different probe sets were determined by investigated using specific probe sets detecting the analyzing five normal control samples from fixed cells and t(11;18)(q21;q21) and the t(14;18)(q32;q21).
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