Structure of the MLT 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.
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.
Baens
M
M
Human Genome Laboratory, Center for Human Genetics-Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium.
Steyls
A
A
Dierlamm
J
J
De Wolf-Peeters
C
C
Marynen
P
P
D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D020169:Caspases; D019457:Chromosome Breakage / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000737:chemistry / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics*; D008969:Molecular Sequence Data; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000737:chemistry / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*
D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein