Author:

Keywords:

Aged, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Female, Gene Amplification, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, bcl-2, Humans, Lymphoma, B-Cell, Lymphoma, Mucosa-Associated Lymphoid Tissue, Male, Middle Aged, Neoplasm Proteins, RNA, Neoplasm, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Translocation, Genetic, Science & Technology, Life Sciences & Biomedicine, Hematology, COMPARATIVE GENOMIC HYBRIDIZATION, LEVEL DNA AMPLIFICATIONS, MARGINAL ZONE LYMPHOMA, NF-KAPPA-B, LOW-GRADE, FOLLICULAR LYMPHOMA, BCL-2 GENE, T(11/18)(Q21,Q21), BCL10, EXPRESSION, Caspases, Lymphoma, B-Cell, Marginal Zone, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

Abstract:

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 expression 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 lymphoma (MZL) with t(14;18)(q32;q21), cytogenetically identical to the translocation involving BCL2, were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloning of both by long-distance inverse polymerase 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 examined the structure and gene expression profile of genomic amplifications involving 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene expression profiling techniques. Using array CGH, 2 peaks of genomic amplification were observed, one centered around BCL2 and the other around MALT1.Ofthe 3 cell lines with MALT1 amplification, 2 showed MALT1 overexpression as assessed by gene profiling, quantitative reverse transcription-polymerase chain reaction (QRT-PCR), and Western blotting. To determine if comparable events occurred 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.