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 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.
Sanchez-Izquierdo
Dolors
D
Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Spain.
Buchonnet
Gerard
G
Siebert
Reiner
R
Gascoyne
Randy D
RD
Climent
Joan
J
Karran
Loraine
L
Marin
Miguel
M
Blesa
David
D
Horsman
Douglas
D
Rosenwald
Andreas
A
Staudt
Louis M
LM
Albertson
Donna G
DG
Du
Ming-Qing
MQ
Ye
Hongtao
H
Marynen
Peter
P
Garcia-Conde
Javier
J
Pinkel
Daniel
D
Dyer
Martin J S
MJ
Martinez-Climent
Jose Angel
JA
D000368:Aged; D020169:Caspases; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D012334:RNA, Neoplasm / Q000032:analysis; D014178:Translocation, Genetic
D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein