MALT B cell lymphomas with t(1;14)(p22;q32) showed a recurrent breakpoint upstream of the promoter of a novel gene, Bcl10. Bcl10 is a cellular homolog of the equine herpesvirus-2 E10 gene: both contain an amino-terminal caspase recruitment domain (CARD) homologous to that found in several apoptotic molecules. Bcl10 and E10 activated NF-kappaB but caused apoptosis of 293 cells. Bcl10 expressed in a MALT lymphoma exhibited a frameshift mutation resulting in truncation distal to the CARD. Truncated Bcl10 activated NF-kappaB but did not induce apoptosis. Wild-type Bcl10 suppressed transformation, whereas mutant forms had lost this activity and displayed gain-of-function transforming activity. Similar mutations were detected in other tumor types, indicating that Bcl10 may be commonly involved in the pathogenesis of human malignancy.

A nasopharyngeal carcinoma tumour (designated C15) propagated in nude mice has been used to generate a large cDNA library that we have analysed for Epstein‐Barr virus (EBV) gene expression. No gross alterations exist in viral DNA from C15 relative to other human isolates and the large deletion present in the B95‐8 ‘prototype’ viral strain established in marmoset cells is not found; C15 contains no linear virion DNA. In the cDNA library, of the six EBV nuclear antigens (EBNAs) expressed in latently infected B‐lymphocytes, only clones for EBNA‐1 are found. These data are confirmed by immunoblotting. Sequence analysis shows the EBNA‐1 mRNA splicing pattern in the carcinoma to differ from that observed in B‐lymphocytes. Further, contrary to observations with B‐cell lines, most viral transcription in the tumour is localized onto the ‘rightmost’ region of the conventional EBV physical map. Transcripts identified corresponding to known genes include those for the latent membrane protein (LMP), the alkaline DNA exonuclease and probably the terminal protein; major transcripts are also derived from the BamHI D fragment and the region deleted in B95‐8 EBV DNA. Novel transcripts have also been identified that proceed in an anti‐sense direction to genes encoding functions associated with replication, such as the viral DNA polymerase. They contain a large, hitherto unidentified, open reading frame in the viral genome that is complementary to the putative function known as BALF3 and a smaller open reading frame complementary to BALF5 (the DNA polymerase gene). From the present studies we can conclude that: (i) EBV transcription patterns in the epithelial cells vary markedly from those identified previously in B‐cells, reflecting differential use of promoters or splicing patterns. (ii) Transcription is tightly regulated and restricted in the C15 tumour with many latent genes, notably EBNAs 2‐6, being ‘switched off.’ (iii) A family of cytoplasmic RNAs are transcribed in an antisense direction to a number of existing open reading frames in the EBV genome. (iv) There are a number of mutations in C15 transcripts relative to the B95‐8 genome, some of which could result in amino acid alterations in proteins.

BCL10 is an apoptotic regulatory molecule identified through its direct involvement in t(1;14)(p22;q32) of mucosa-associated lymphoid tissue (MALT) lymphoma. We examined BCL10 protein expression in various normal tissues and B-cell lymphomas by immunohistochemistry of formalin-fixed and paraffin-embedded tissues using mouse BCL10 monoclonal antibodies. BCL10 protein was expressed in lymphoid tissue but not in 21 various other tissues with the exception of breast. In normal B-cell follicles, the protein was expressed abundantly in the germinal center B cells, moderately in the marginal zone, but only weakly in the mantle zone B cells. Irrespective of their stage of B-cell maturation, BCL10 was predominantly expressed in the cytoplasm. In contrast, each of the four MALT lymphomas with t(1;14)(p22;q32) showed strong BCL10 expression in both the nucleus and cytoplasm. Twenty of 36 (55%) MALT lymphomas lacking the translocation exhibited BCL10 expression in both the nucleus and cytoplasm although at a much lower level, whereas the remaining 16 cases displayed only cytoplasmic BCL10. Unlike MALT lymphoma, both follicular and mantle cell lymphomas generally displayed BCL10 expression compatible to their normal cell counterparts. Our results show differential expression of BCL10 protein among various B-cell populations of the B-cell follicle, indicating its importance in B-cell maturation. The subcellular localization of BCL10 was frequently altered in MALT lymphoma in comparison with its normal cell counterparts, suggesting that ectopic BCL10 expression may be important in the development of this type of tumor.

The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (

Chromosomal translocation t(6;14)(p21.1; q32.3) has been reported as a rare but recurrent event not only in myeloma and plasma cell leukemia but also in diffuse large B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL]) and splenic lymphoma with villous lymphocytes (SLVL); however, the nature of the target gene(s) has not been determined. This study identified t(6; 14)(p21.1;q32.3) in 3 cases of transformed extranodal marginal zone B-NHL, in 1 case of SLVL, and in 1 case of a low-grade B-cell lymphoproliferative disorder. In a sixth case, a CD5 ؉ DLBCL, the translocation was identified by molecular cloning in the absence of cytogenetically detectable change. Two chromosomal translocation breakpoints were cloned by using long-distance inverse polymerase chain reaction methods. IntroductionThe lymphomas and leukemias of mature B cells are a biologically and histologically heterogeneous group of malignancies. 1 Their molecular pathogenesis for the most part remains unknown, although cloning of chromosomal translocations targeted to the immunoglobulin (IG) loci continues to allow the identification of novel dominant oncogenes and to define new pathogenic mechanisms. 2 These translocations result in the deregulated expression of genes involved in several pathways, including the control of programmed cell death (apoptosis) and proliferation.IG translocations that involve genes controlling progression through the cell cycle have been described. Cyclin D1 (CCND1) on chromosome 11q13 is involved in the t(11;14)(q13;q32.3). This translocation is found in nearly all cases of mantle cell lymphoma but also in some cases of myeloma, in marginal zone malignancies, such as splenic lymphoma with villous lymphocytes (SLVL), and in B-cell prolymphocytic leukemia. [3][4][5][6] The cyclin-dependent kinase gene (CDK6) in chromosome band 7q22 is involved in t(7;14)(q22;q32) or more commonly in t(2;7)(p12;q22); these translocations appear to be specific for a subset of SLVL. 7,8 The involvement of the cell-cycle regulatory genes in marginal zone B-cell malignancies was unanticipated, because they are characteristically indolent diseases. Whether these genes might have functions in B-cell differentiation other than cell-cycle regulation in mature B cells is not yet clear; cyclin D3 expression, for example, is associated with differentiation of some cell types. 9 Cytogenetic abnormalities of chromosome band 6p21 reported in mature B-cell malignancies are various and include translocations, amplifications, and deletions. 10,11 Such translocations in diffuse large B-cell lymphoma (DLBCL) often involve the BCL6 gene on chromosome band 3q27 and may juxtapose BCL6 with either the histone H4 gene or the PIM1 oncogene. 12,13 The t(6;14)(p12ϳp21;q32) has been previously reported in a variety of B-cell malignancies, principally in myeloma and plasma cell leukemia but also in DLBCL and splenic marginal zone lymphomas (SMZLs). 14-18 Here we report the recurrent involvement of a For personal use only. on May 12, 2018. by gues...