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BCL10 Gene Mutations Rarely Occur in Lymphoid Malignancies

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BCL10 Gene Mutations Rarely Occur in Lymphoid Malignancies Leukemia (2000) 14, 905–908 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu BCL10 gene mutations rarely occur in lymphoid malignancies S Luminari1, D Intini1, L Baldini1, E Berti2, F Bertoni3, E Zucca3, L Cro1, AT Maiolo1, F Cavalli3 and A Neri1 1Laboratorio di Ematologia Sperimentale e Genetica Molecolare, Servizio di Ematologia, Istituto di Scienze Mediche, and 2Istituto di Scienze Dermatologiche, Universita` di Milano, Ospedale Maggiore IRCCS, Milan, Italy; and 3Istituto Oncologico della Svizzera Italiana, Ospedale San Giovanni, Bellinzona, Switzerland BCL10, a gene involved in apoptosis signalling, has recently ability to activate NF-kB, do not induce apoptosis, and have been identified through the cloning of chromosomal break- gain-of-function transforming activity.1,2 On the basis of this points in extranodal (MALT-type) marginal zone lymphomas carrying the t(1;14)(p22;q32) translocation. BCL10 was also evidence, it has been suggested that BCL10 may represent a found mutated in these cases as well as in other types of major target gene for inactivation in a large variety of human lymphoid and solid tumors, suggesting that its inactivation cancers.1 However, more recent data have failed to validate may play an important pathogenetic role; however, this has this notion since no somatic BCL10 mutations have been been questioned by recent studies showing a lack of somatic found in genomic DNAs from other series of patients with mutations in human cancers. We report the mutation analysis lymphoid or solid tumors.8–13 Given the fact that the initial of exons 1–3 of the BCL10 gene in DNAs from 228 cases of 1,2 lymphoid malignancies (30 B cell chronic lymphocytic leukem- reports made use of cDNAs rather than DNAs, it has been ias, 123 B and 45 T non-Hodgkin’s lymphomas and 30 multiple suggested that post-transcriptional modifications of the BCL10 myelomas). Somatic mutations were detected in four cases gene may explain this discrepancy.14 (<2%): one small lymphocytic, one follicular and two diffuse As far as we know, among lymphoid malignancies, somatic large cell lymphomas. The mutations were all within exon 3 and mutations affecting the BCL10 gene have been reported in 21 have not been previously reported. Our data suggest that of 135 B cell tumors (not well specified histologically) by Peng BCL10 mutations may play only a limited role in the pathogen- et al in a recent abstract,15 but not in any of MALT lymphomas esis of lymphoid neoplasms. Leukemia (2000) 14, 905–908. 8 Keywords: BCL10; non-Hodgkin’s lymphoma; multiple myeloma; or 15 FLs analyzed by Fakruddin et al. To address the role mutation analysis of BCL10 in lymphoid neoplasms more extensively, we inves- tigated mutations in exons 1, 2 and 3 of the gene by single- strand conformation polymorphism (SSCP) and direct DNA Introduction sequencing in a panel of 228 cases, including 30 B cell chronic lymphocytic leukemias (B-CLL), 123 B cell non- The BCL10 gene was recently identified through its direct Hodgkin’s lymphomas (NHL), 45 T cell NHL and 30 multiple involvement in the t(1;14)(p22;q32) chromosomal trans- myelomas (MM). location, which is recurrently associated with extranodal (MALT-type) marginal zone lymphomas.1,2 The BCL10 gene, also known as CIPER,3 mE104 and c-CARMEN,5 is the cellular Materials and methods homolog of the equine herpes virus-2 E10;6 both encode pro- teins containing an amino terminal caspase recruitment Patients domain (CARD) similar to that found in some apoptotic regu- latory proteins.7 The CARD is thought to mediate BCL10 A total of 228 lymphoid tumors, including 30 B-CLL, 123 B- dimerization, thus allowing the binding and activating cleav- NHL of different hystologic subtypes, 45 T-NHL and 30 MM age of the zymogen pro-caspase-9.6 BCL10 also contains a (see Table 1), were selected from the files of the Hematology carboxy terminus rich in Ser/Thr residues whose function is Service, Ospedale Maggiore (Milan, Italy) and the Oncology still unknown.3 The BCL10 gene transcribes a 2.8 kb mRNA Institute of Southern Switzerland (Bellinzona, Switzerland). that is expressed at relatively low levels in all normal tissues.2 The diagnosis was made according to previously published 16 Functional studies have indicated that BCL10 activates NF-kB, criteria. DNAs were obtained from fresh or frozen patho- induces apoptosis in MFCF and 293 cells, and is able to logic samples (peripheral blood, bone marrow or tissues) by suppress in vitro transformation.1–5 phenol/chlorophorm extraction. Neoplastic clonal popu- As a consequence of the chromosomal translocation, the lations could be identified in the samples on the basis of cyto- BCL10 gene was found to be juxtaposed to the immunoglob- fluorimetric immunophenotypic and/or antigen receptor genes ulin heavy chain (IGH) locus and overexpressed in t(1;14) rearrangement analyses; some of the samples investigated in 17–19 positive MALT lymphomas. In these cases, BCL10 cDNAs also this study have been previously reported. DNAs from per- included a large variety of mutations, most leading to trunc- ipheral blood leukocytes of 45 healthy donors and 20 patients ation either in or carboxy terminal to the CARD.1,2 Mutations with thrombocythemia were also included in the study as have also been found in other types of lymphoid tumors, such controls. as follicular lymphomas (FL), and cell lines derived from solid tumors, such as germ cell tumors and mesotheliomas.1 It has been shown that truncated forms of BCL10 maintain the PCR-SSCP and direct DNA sequencing Exons 1, 2 and 3 of the BCL10 gene were amplified by poly- merase chain reaction (PCR) from genomic DNA using the Correspondence: A Neri, Servizio Ematologia, Istituto di Scienze Med- five primer sets (1, 2.1, 2.2, 3.1 and 3.2) described by Willis iche, Universita` di Milano, Ospedale Maggiore di Milano, IRCCS, Via 1 Francesco Sforza 35, 20122 Milano, Italy; Fax: +39–02–55012111 et al. The PCR conditions were optimized for each set of pri- 17 SL and DI contributed equally to this work mers. For SSCP analysis, 20 µl of PCR were mixed with an Received 27 October 1999; accepted 17 December 1999 equal volume of formamide loading buffer, heated at 95°C for BCL10 mutations in lymphoid tumors S Luminari et al 906 Table 1 Frequency of BCL10 mutations in lymphoid malignancies a similar SSCP pattern was observed in cases LB1637 and LB1624 (a FL with a BCL2 gene rearrangement and a small Diagnosis Positivea/Sample lymphocytic lymphoma, respectively), whereas different pat- tested terns were found in two cases of diffuse large cell lymphomas (LB1929 and LB1634 without any involvement of the BCL2, B cell tumors BCL6 or TP53 genes) (Figure 1a). Direct DNA sequencing in Chronic lymphocytic leukemia 0/30 Small lymphocytic lymphoma 1/14 cases LB1637 and LB1624 revealed a nucleotide change (T to Lymphoplasmacyotoid lymphoma 0/6 A transversion) at the second position of codon 174 resulting Follicular lymphoma 1/33 in a stop codon; in case LB1929, a nucleotide insertion, Marginal zone lymphoma 651insA, leading to a frameshift and putative truncated pro- Extranodal gastric 0/21 tein of 218 aa; and in case LB1634, a G to C transversion at b Extranodal other than gastric 0/7 the second position of codon 226, resulting in an Arg-Thr Nodal 0/5 Mantle cell lymphoma 0/19 amino acid substitution. Finally, in two cases (LB1637 and Diffuse large cell lymphoma 2/18 LB1634), we could match the tumor DNA with DNA from Multiple myeloma 0/30 their respective peripheral blood cells. It is worth noting that T cell tumors the mutated pattern was not found in the normal DNA (data Mycosis fungoides 0/32 not shown), thus indicating the somatic origin of the mutations Sezary syndrome 0/4 in these two cases, as well as in case LB1624 which had the Chronic lymphocytic leukemia 0/5 Angioimmunoblastic lymphoma 0/4 same mutation as case LB1637. BCL10 mutations were thus detected in four cases (3%; aOnly non-polymorphic changes are indicated. 95% CI, 1–7%) of the 153 B cell malignancies (but not in the bIncluding marginal splenic lymphoma (four cases), marginal T-NHL and MM) and, despite their very limited number, did lymphoma of the lung (one case), marginal lymphoma of the not appear to be associated with any particular histologic or conjunctiva (two cases). malignancy-grade subtype. It is worth noting that no BCL10 mutations were identified in the group of 28 MALT lym- phomas, a finding in agreement with that reported by Fakrud- 5 min, and separated in a 0.75× MDE electrophoresis gel din et al.8 It cannot be excluded that we may have missed (FMC, Rockland, ME, USA) under 40 W constant power for some BCL10 mutations, but SSCP is generally considered to 16 h at 5°C. The bands were visualized by silver staining. The be an efficient and sensitive method, as is further confirmed colonic carcinoma-derived Lovo cell line mutated at codon by the fact that we and others have been able to detect a 46 of the BCL10 gene,1 was used as a positive control for number of single-base polymorphisms and the previously SSCP sensitivity; as described in previous reports,17 our SSCP described mutation in the Lovo cell line.8–13 conditions make it possible to also detect a monoallelic As mentioned above, we have evidence for the somatic ori- BCL10 mutation in about 10% of a given cell population (data gin of the mutations in three cases. Although we cannot rule not shown).
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