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). The cytospin preparations from frozen and paraffin-embedded t(11;18)(q21;q21) was analyzed with PAC clones 59N7 (MLT/ tissue. The cutoff levels were defined by the mean plus three MALT1 gene) in combination with 166G16 (API2 gene).5 The standard deviations of the respective result in the experiments novel t(14;18)(q32;q21) was shown with PACs 59N7 and with the normal controls. The cutoff levels were determined as follows: MLT/MALT1-assay (PAC 59N7 and PAC 117B5) on fixed cells 4.9%, on frozen material 6.3%, on paraffin- embedded material 5%; t(14;18) assay (PAC 59N7 and cosmid Ca1) on fixed cells 4.6%, on frozen material 6.5%, on paraffin- embedded material 6.6%; and t(11;18) assay (PAC 59N7 and PAC 166G16) on fixed cells 4.1%, on frozen material 4.4%, on paraffin-embedded material 4.4%.

Results

We analyzed 108 MZBCL including 72 extranodal, 17 nodal, and 19 splenic cases with a novel two-color interphase FISH assay using two PAC clones 59N7 and PAC 117B5 flanking the MLT/MALT1 gene (Figure 1a). Separated MLT/MALT1-specific signals, indicating a structural chromosomal abnormality invol- ving MLT/MALT1, were observed in 19 cases, all of which Figure 1 Schematic illustration of the chromosomal region 18q21 represented extranodal MALT lymphomas (Figure 1b). There- and representative example of FISH analysis. (a) PAC contig spanning fore, the prevalence of translocations involving MLT/MALT1 18q21 with PAC 117B5 and PAC 59N7 flanking the MLT/MALT1 was 26% (19 of 72 cases) in the group of extranodal MALT gene. (b) Interphase FISH using two PAC clones flanking the MLT/ lymphomas, whereas none of the nodal and splenic MZBCL MALT1 gene, PAC 117B5 (green) and PAC 59N7 (red). In normal cells, the two differentially labeled probes display two fusion signals, revealed any MLT/MALT1-associated translocation (Table 1). whereas in the presence of a disruption of MLT/MALT1, that is, by a The MALT lymphomas with separated MLT/MALT1-specific translocation, two separated signals and one fusion signal can be seen. signals were confined to the following organs: stomach (n ¼ 7), Abnormal cells are indicated with arrows. intestine (n ¼ 3), parotid gland (n ¼ 6), lung (n ¼ 1), submaxillary

Leukemia Detection of abnormalities involving MLT/MALT1 by FISH EM Murga Penas et al 2227 Table 1 Detection of t(11;18)(q21;q21) and t(14;18)(q32;q21) using interphase FISH in 108 cases of marginal zone B-cell lymphoma

Diagnosis No. of analyzed cases MLT/MALT1 assay t(11;18) assay t(14;18) assay No. of positive cases No. of positive cases No. of positive cases

Extranodal MZBCL of MALT type 72 19 12 7 Stomach 31 7 7 0 Intestine 5 3 3 0 Lung 1 1 1 0 Submaxillary gland 1 1 1 0 Parotid gland 28 6 0 6 Conjunctiva 3 1 0 1 Breast 1 0 0 0 Skin 1 0 0 0 Thymus 1 0 0 0

Nodal MZBCL 17 0 0 0 Splenic MZBCL 19 0 0 0

Table 2 Summary of all marginal zone B-cell lymphomas displaying copy number changes of chromosome 18

Case Diagnosis Number of hybridization signals

Chromosome 18 Chromosome 11

MLT/MALT1 BCL2 Centromere 18 Centromere 11

1 MALT parotid 5 5 5 2 2 MALT stomach 4 4 4 2 3 MALT parotid 3 3 3 2 4 MALT breast 3 3 3 2 5 Nodal MZBCL 3 3 3 2 6 Nodal MZBCL 3 3 3 2 7 Splenic MZBCL 3 3 3 2 8 Splenic MZBCL 3 3 3 2 9 Splenic MZBCL 3 3 3 2 10 Splenic MZBCL 3 3 3 2 11 Splenic MZBCL 3 3 3 2 12 Splenic MZBCL 3 3 3 2 13 Splenic MZBCL 3 3 3 2 14 MALT stomach 1 1 2 2 15 MALT stomach 1 1 2 2 gland (n ¼ 1), and conjunctiva (n ¼ 1). The latter cases were MZBCL (seven cases with trisomy 18) (Table 2). The splenic further analyzed by interphase FISH for the presence of the MZBCL showed the highest frequency of trisomy 18 with seven t(11;18)(q21;q21) and the t(14;18)(q32;q21). The t(11;18) was out of 19 cases (37%) revealing this abnormality. In all 13 cases found in 12 cases (17% of the MALT lymphomas) and the with aneuploidy of chromosome 18, only two centromere t(14;18) was detected in seven cases (10% of the MALT 11-specific hybridization signals were detected (Table 2). lymphomas) (Table 1). The frequency at which these transloca- Deletions involving MLT/MALT1 and BCL2, but not the tions occurred varied significantly with the primary location of centromeric region of chromosome 18, were found in two disease. The t(11;18)-positive cases comprised mainly MALT MALT lymphomas (Table 2). lymphomas of the gastrointestinal tract (28% of these cases), one MALT lymphoma of the lung (only one case analyzed), and one MALT lymphoma of the submaxillary gland (only one case analyzed). The t(14;18) occurred exclusively in MALT lympho- Discussion mas located in the parotid gland and the conjunctiva (23% of these cases) (Table 1). An autoimmune myoepithelial sialade- This is the first study that screened a series of MZBCL for all nitis (MESA) associated with Sjo¨gren’s syndrome was diagnosed kinds of translocations and amplifications/over-representations in all of the six patients with a MALT lymphoma of the parotid involving the recently discovered MLT/MALT1 gene on chromo- gland. some 18q21. To do so, we have developed an undirected dual- Amplification of MLT/MALT1 was not found in any of the 108 color interphase FISH assay with two PAC clones flanking the MZBCL. However, trisomy or polysomy of chromosome 18 MLT/MALT1 gene. A separation of the hybridization signals of revealed by three to five MLT/MALT1-, BCL2-, and centromere the two PAC clones indicates a disruption of the MLT/MALT1 18-specific hybridization signals was observed in 13 cases, gene, for example by a translocation. This assay can easily be including four MALT lymphomas (two cases with trisomy 18, applied to fresh and archival tumor tissue, as paraffin-embedded one case with tetrasomy 18, one case with pentasomy 18), two tissue, and therefore enables the retrospective and prospective nodal MZBCL (two cases with trisomy 18), and seven splenic analysis of large series.

Leukemia Detection of abnormalities involving MLT/MALT1 by FISH EM Murga Penas et al 2228 Using this assay we have analyzed 108 MZBCL, including 72 Since the MLT/MALT1 gene lies about 5 Mb centromeric to extranodal MALT lymphomas from various localizations, 17 the BCL2 gene, its involvement in the 18q21 amplicon observed nodal, and 19 splenic MZBCL. Separated hybridization signals in several subtypes of NHL has been suggested.17 However, in of the MLT/MALT1 flanking probes were found in 19 cases, all of our study, amplifications of MLT/MALT1 were not observed in which represented extranodal MALT lymphomas. None of the any of the cases. In the recently published investigation by nodal or splenic lymphomas showed a translocation involving Sa´nchez-Izquierdo et al,17 only one of the five MALT MLT/MALT1. These findings suggest that chromosomal translo- lymphomas and none of the 35 splenic MZBCL analyzed by cations involving MLT/MALT are exclusively associated with interphase FISH revealed a low-level amplification of MLT/ extranodal MZBCL of the MALT type. Similar results have been MALT1 and BCL2 (five copies of each). In the same study, published for the t(11;18), which specifically characterizes amplification of MLT/MALT1 without coamplification of BCL2 extranodal MALT lymphomas and has not been observed in any was detected by array CGH in two of the 40 analyzed cell lines other subtype of NHL.2,4,5,11 In order to determine the unknown derived from various subtypes of B-cell NHL. These two cell translocation partner of MLT/MALT1, all 19 cases showing lines were derived from a MZBCL and a Burkitt’s lymphoma, separated MLT/MALT1-specific hybridization signals were respectively, and displayed high-levels of MLT/MALT1 RNA and further analyzed by FISH with probes sets detecting the protein expression.17 The authors conclude that MLT/MALT1 t(11;18)(q21;q21) and t(14;18)(q32;q21), respectively. In all 19 and BCL2 are independent targets of amplification in NHL. cases, either the t(11;18) or the t(14;18) were detected. No other In our study, trisomy or polysomy of chromosome 18 was structural chromosomal abnormalities involving MLT/MALT1 observed in 13 cases, including four extranodal MALT were found. The t(11;18) was observed in 10 gastrointestinal, lymphomas, two nodal, and seven splenic MZBCL (Table 2). one pulmonary, and one MALT lymphoma of the submaxillary These data are in accordance with previous reports, which glands. The novel t(14;18) rearranging the MLT/MALT1 and IGH showed a similar prevalence of trisomy 18 in MZBCL.25–27 The genes was found in seven MALT lymphomas of the parotid gland genetic mechanism by which aneuploidy of chromosome 18, and one MALT lymphoma of the ocular conjunctiva. These data especially trisomy 18, may contribute to neoplastic transforma- demonstrate for the first time that the t(11;18)(q21;q21) and tion or disease progression of MZBCL is not known. A gene t(14;18)(q32;q21) represent the two main translocations invol- dosage effect resulting from a higher copy number of MLT/ ving MLT/MALT1 in MALT lymphomas and that other MLT/ MALT1 could be suggested. MALT1-associated rearrangements are at least rare. Interestingly, two of our cases revealed a deletion of MLT/ In the present study, the t(11;18) was found in 17% of all MALT1 and BCL2, a finding that has not been described so far analyzed MALT lymphomas, including 28% of MALT lympho- (Table 2). The pathogenetic importance of an MLT/MALT1 mas of the gastrointestinal tract, one MALT lymphoma of the deletion remains to be determined. lung, and one MALT lymphoma of the submaxillary gland. We conclude, that the applied interphase FISH assay is an Interestingly, in none of the MALT lymphomas infiltrating these effective method to detect translocations, amplifications and organs the t(14;18) was detected. The incidence of the t(11;18) over-representations of MLT/MALT1. The translocations in our study is comparable with previous data reported in the t(11;18)(q21;q21) and t(14;18)(q21;q32) are the main structural literature.5,10,11,14,24 Ye and co-workers screened 417 cases of aberrations involving MLT/MALT1 in MALT lymphomas, MALT lymphomas from eight major sites by RT-PCR for the whereas true amplifications of MLT/MALT1 occur rarely in presence of the t(11;18) and found this translocation at highest MZBCL. frequencies in MALT lymphomas from the lung (38%) and stomach (24%), and in moderate frequencies in those from the Acknowledgements conjunctiva (19%) and orbit (14%). However, the t(11;18) was only rarely found in MALT lymphomas from the salivary gland This work was supported by Grant 70-3019Di3 from the Deutsche (1%) and was absent in those from the thyroid, skin, liver, and Krebshilfe/Dr Mildred Scheel Stiftung fu¨r Krebsforschung. other rare site.14 The prevalence of the t(14;18) in the present study was 10% in the group of MALT lymphomas and 23% in the group of MALT References lymphomas involving the parotid gland or the conjunctiva. Interestingly, we found a strong correlation between the 1 Auer IA, Gascoyne RD, Connors JM, Cotter FE, Greiner TV, Sanger occurrence of the two main MLT/MALT1-associated transloca- WG et al. t(11;18)(q21;q21) is the most common translocation in tions, t(11;18) and t(14;18), and the site of origin of the MALT lymphomas. Ann Oncol 1997; 8: 979–985. underlying MALT lymphoma. The t(14;18) was most frequently 2 Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U et al. The t(11;18)(q21;q21) chromosome translocation is a found in MALT lymphomas of the parotid gland, which rarely frequent and specific aberration in low-grade but not high-grade harbor the t(11;18), and was absent in pulmonary and malignant non-Hodgkin’s lymphomas of the mucosa-associated gastrointestinal MALT lymphomas, which showed the highest lymphoid tissue (MALT-)type. Cancer Res 1997; 57: 3944–3948. frequencies of the t(11;18). A similar correlation has been found 3 Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, in a recent study, where the t(14;18)(q32;q21) has been detected Hernandez JM, Hossfeld DK et al. The apoptosis inhibitor gene in MALT lymphomas arising from the liver, ocular adnexa, API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with MALT lymphomas. Blood 1999; parotid gland, and skin but not in any of the MALT lymphomas 93: 3601–3609. 18 arising from the gastrointestinal tract, lung, thyroid, and breast. 4 Rosenwald A, Ott G, Stilgenbauer S, Kalla J, Bredt M, Katzenberger Together, these data would indicate that the genetic abnorm- T et al. Exclusive detection of the t(11;18)(q21;q21) in extranodal alities in MALT lymphomas reflect their site of origin and marginal zone B cell lymphomas (MZBL) of MALT type in contrast possibly either environmental or autoimmune causes. Gastric to other MZBL and extranodal large B cell lymphomas. Am J Pathol MALT lymphomas usually develop in a background of chronic 1999; 155: 17–1821. 5 Dierlamm J, Baens M, Stefanova-Ouzounova M, Hinz K, Helicobacter pylori gastritis, whereas MALT lymphomas of the Wlodarska I, Steyls A et al. Detection of t(11;18)(q21;q21) by parotid glands are frequently found in patients with Sjo¨grens’ interphase fluorescence in situ hybridization using API2 and MLT syndrome and autoimmune MESA, as in the present study. specific probes. Blood 2000; 96: 2215–2218.

Leukemia Detection of abnormalities involving MLT/MALT1 by FISH EM Murga Penas et al 2229 6 Dierlamm J. Genetic abnormalities in marginal zone B-cell 17 Sanchez-Izquierdo D, Buchonnet G, Siebert R, Gascoyne RD, lymphoma. Haematologica 2003; 88: 8–12. Climent J, Karran L et al. MLT/MALT1 is deregulated by both 7 Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H chromosomal translocation and amplification in B-cell non- et al. A novel gene, MALT1 at 18q21, is involved in Hodgkin lymphoma. Blood 2003; 101: 4539–4546. t(11;18)(q21;q21) found in low-grade B-cell lymphoma of muco- 18 Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G sa-associated lymphoid tissue. Oncogene 1999; 18: 5785–5794. et al. T(14;18)(q32;q21) involving IGH and MLT/MALT1 is a 8 Morgan JA, Yin Y, Borowsky AD, Kuo F, Nourmand N, Koontz JI frequent chromosomal aberration in MALT lymphoma. Blood et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated 2003; 101: 2335–2339. lymphoid tissue (MALT) lymphoma lie within or near the 19 Joos S, Haluska FG, Falk MH, Henglein B, Hameister H, Croce CM previously undescribed gene MALT1 in chromosome 18. Cancer et al. Mapping chromosomal breakpoints of Burkitt’s (8;14) Res 1999; 59: 6205–6213. translocations far upstream of c-myc. Cancer Res 1992; 52: 9 Baens M, Steyls A, Dierlamm J, De Wolf-Peeters C, Marynen P. 6547–6552. Structure of the MLT gene and molecular characterization of the 20 Kallioniemi OP, Kallioniemi A, Kuriso W, Thor A, Chen LC, Smith genomic breakpoint junctions in the t(11;18)(q21;q21) of marginal HS et al. ERBB2 amplification in breast cancer analyzed by zone B-cell lymphomas of MALT type. Genes Chromosomes fluorescence in situ hybridization. Proc Natl Acad Sci USA 1992; Cancer 2000; 29: 281–291. 89: 5321–5325. 10 Kalla J, Stilgenbauer S, Schaffner C, Wolf S, Ott G, Greiner A et al. 21 Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keina¨nen R, Heterogeneity of the API2-MALT1 gene rearrangement in MALT- Palmberg C et al. In vivo amplification of the androgen receptor type lymphoma. Leukemia 2000; 14: 1967–1974. gene and progression of human prostate cancer. Nat Genet 1995; 11 Remstein ED, James CD, Kurtin PJ. Incidence and subtype 9: 401–406. specificity of API2-MALT1 fusion translocations in extranodal, 22 Silverman GA, Green ED, Young RL, Jockel JI, Domer PH, nodal, and splenic marginal zone lymphomas. Am J Pathol 2000; Korsmeyer SJ. Meiotic recombination between yeast artificial 156: 1183–1188. chromosomes yields a single clone containing the entire 12 Uren AG, O’Rourke K, Aravind L, Pisabarro MT, Seshagiri S, BCL2 protooncogene. Proc Natl Acad Sci USA 1990; 87: Koonin EV et al. Identification of paracaspases and metacaspases: 9913–9917. two ancient families of caspase-like proteins, one of which plays a 23 Dierlamm J, Wlodarska I, Michaux L, La Starza R, Zeller W, key role in MALT lymphoma. Mol Cell 2000; 6: 961–967. Meccuci C et al. Successful use of the same slide for consecutive 13 Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed fluorescence in situ hybridization experiments. Genes Chromo- ME, Chen FF et al. Bcl10 and MALT1, independent targets of somes Cancer 1996; 16: 261–264. chromosomal translocation in MALT lymphoma, cooperate 24 Motegi M, Yonezumi M, Suzuki H, Suzuki R, Hosakawa Y, Hosaka in a novel NF-kB signaling pathway. J Biol Chem 2001; 276: S et al. API2-MALT1 chimeric transcripts involved in mucosa- 19012–19019. associated lymphoid tissue type lymphoma predict heterogeneous 14 Ye H, Liu H, Attygalle A, Wotherspoon AC, Nicholson AG, products. Am J Pathol 2000; 156: 807–812. Charlotte F et al. Variable frequencies of t(11;18)(q21;q21) in 25 Dierlamm J, Pittaluga S, Wlodarska I, Stul M, Thomas J, Boogaerts MALT lymphomas of different sites: significant association with M et al. Marginal zone B-cell lymphomas of different sites share CagA strains of H. pylori in gastric MALT lymphoma. Blood 2003; similar cytogenetic and morphologic features. Blood 1996; 87: 102: 1.012–1.018. 299–307. 15 Liu H, Ye H, Ruskone-Fourmestraux A, De Jong D, Pileri S, Thiede 26 Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, C. t(11;18) is a marker for all stage gastric MALT lymphomas that Michaux L et al. Characteristic pattern of chromosomal gains and will not respond to H. pylori eradication. Gastroenterology 2002; losses in marginal zone B cell lymphoma detected by comparative 122: 1286–1294. genomic hybridization. Leukemia 1997; 11: 747–758. 16 Ye H, Liu H, Radere M, Chott A, Ruskone-Fourmestraux A, 27 Wotherspoon AC, Finn TM, Isaacson PG. Trisomy 3 in low-grade Wotherspoon A et al. High incidence of t(11;18)(q21;q21) in B-cell lymphomas of the mucosa associated lymphoid tissue. Helicobacter pylori-negative gastric MALT lymphomas. Blood Blood 1995; 85: 2000–2004. 2003; 101: 2547–2550.

Leukemia