Structure of theMLT gene and molecular characterization of the genomic breakpoint junctions in the t(11;18)(q21;q21) of marginal zone B-cell lymphomas of MALT type

Abstract

The t(11;18)(q21;q21) between the inhibitor of apoptosis API2 and the MLT gene is a distinct feature of marginal zone B‐cell lymphomas of MALT‐type. Hitherto the chimeric API2‐MLT transcripts are all “in‐frame” and predominantly fuse exon 7 of API2 to different MLT exons. Recurrent chromosomal translocations are common in lymphoid neoplasms and might represent by‐products of the rearrangement processes generating antigen receptor diversity. The genomic structure of the MLT gene was determined to facilitate amplification of the genomic breakpoint junctions from 5 MALT‐type lymphomas with t(11;18). Their sequence analysis showed scattering of the chromosome 11 breakpoints in intron 7 of API2 whereas rearrangements in MLT occurred in intron 2, 4, 7, or 8, respectively. Sequences around the junctions did not display recognition signal sequences mediating lymphocytic V(D)J recombination or other sequence motifs associated with recombination. The breakpoints occurred in a copy of an AluSx repeat in three cases, but interchromosomal Alu‐mediated homologous recombination could be ruled out as the repeat resided only on one of the participating chromosomes. The t(11;18) was associated with a deletion in 4 out of 5 cases, ranging in size from 53 bp up to more than 200 kb. These deletions were observed on one or sometimes both derivative chromosomes that might indicate the susceptibility of these regions for breakage. Our data suggest that the API2‐MLT fusion might result from a non‐homologous end joining event after multiple double‐strand breaks. The clustering of breaks in intron 7 of API2 and the consistent “in frame” API2‐MLT fusions could therefore reflect certain functional constraints crucial for clonal outgrowth. © 2000 Wiley‐Liss, Inc.

The pathogenesis of MALT lymphomas: where do we stand?

“…27 The fusion-junctions at the transcript level are well characterized (Figure 1). 3 All API2 breakpoints are located downstream of the third BIR domain but upstream of the RINGfinger motif, with more than 90% of the breakpoints being located in intron 7, just proximal of the CARD domain, indicating that a common mechanism generates this rearrangement. Conversely, the breakpoints within the MALT1 coding DNA are more variable, occurring in four different introns 2,4,7,8 that are located upstream of the caspase-like domain.…”

“…28 So far, studies have failed to show a specific sequence-mediated chromosomal recombination mechanism involved in the t(11;18)(q21;q21). 3 t(1;14)(p22;q32)…”

“…As such, several genetic aberrations have been identified in MALT lymphomas, some of which appear to be specific for, or at least closely related to, this subtype of MZ lymphoma: the chromosomal translocations t(1;14)(p22;q32), t(14;18)(q32; q21), t(11;18)(q21;q21) and t(3;14)(p13;q32) are all known to occur with variable frequencies in MALT lymphomas, resulting in IGH-BCL10, IGH-MALT1, API2-MALT1 and IGH-forkhead box protein P1 (FOXP1) rearrangements, respectively. [3][4][5][6] The oncogenic activity of t(1;14)(p22;q32), t(14;18)(q32;q21) and t(11;18)(q21;q21) is linked to the involvement of the BCL10 and MALT1 proteins in the antigen-receptor-mediated activation of nuclear factor-kB (NF-kB), which is the transcription factor of a number of survival-and proliferation-related genes in B cells. 7 The oncogenic role of the IGH-FOXP1 fusion transcript is unknown.…”

Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas

“…3,7,8 The pathogenetic relevant event involves the derivative chromosome 11 and leads to linkage of the three baculovirus IAP repeat (BIR) domains present in the N-terminus of API2 and a variable part of MLT/MALT1, which always contains the caspase p20-like domain. 3,7,[9][10][11] The chimeric protein effectively activates NF-kB, a potential prosurvival signal in B cells. 12,13 The t(11;18)(q21;q21) has mainly been observed in lowgrade MALT lymphomas of the gastrointestinal tract and the lung.…”

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

“…For one of these cases (LL29, belonging to group B), the break point at the genomic level was situated close to the 3 0 end of intron 7 (4724 bp in size) just upstream (680 bp) of exon 8 of MALT1. 29 The exact location of the MALT1 break point in intron 7 was not mapped for the three other cases. When we next used Toucan to analyze intron 7 of MALT1, 30 we found one region (from 2559 to 2467 bp 5 0 of exon 8) that was 90% conserved in mouse, indicating a possible regulatory function.…”