NEOPLASIA MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma

The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30 % of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expres-sion may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lym-phoma (MZL) with t(14;18)(q32;q21), cyto-genetically identical to the translocation involving BCL2, were shown by fluores-cence in situ hybridization (FISH) to in-volve MALT1, which lies about 5 Mb cen-tromeric of BCL2. Molecular cloning of both by long-distance inverse polymer-ase chain reaction showed breakpoints lying 1 to 2 kilobase (kb) centromeric of the first 5 MALT1 exon; both cases showed MALT1 overexpression at either RNA or protein levels. Second, we exam-ined the structure and gene expression profile of genomic amplifications involv-ing 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene ex-pression profiling techniques. Using ar-ray CGH, 2 peaks of genomic amplifica-tion were observed, one centered around BCL2 and the other around MALT1. Of the 3 cell lines with MALT1 amplification, 2 showed MALT1 overexpression as as-sessed by gene profiling, quantitative re-verse transcription–polymerase chain re-action (QRT-PCR), and Western blotting. To determine if comparable events oc-curred in primary MALT and splenic MZL tumors, 40 cases were analyzed by FISH or QRT-PCR; genomic amplification and MALT1 overexpression were seen in 2 cases. Together, these data implicate MALT1 as a dominant oncogene that may play a role in the pathogenesis of B-NHL