Differential expression of NF-κB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism

Abstract

Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/ BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-jB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-jB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-jB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocationnegative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-jB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.

RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

“…Most of the KIF1Bβ-induced, DHX9-dependent targets were IFN-induced or IFN-related, consistent with earlier reports implicating DHX9 in transcriptional regulation of IFN-α-inducible genes ( 22 ). Some of these genes are known NF-κB downstream targets (23)(24)(25), in line with earlier observations demonstrating a DHX9-NF-κB interaction resulting in the transactivation of specific promoters ( 18 , 26 ). In addition, the proapoptotic XIAP-associated factor 1 ( XAF1 ) was identified ( Fig.…”

A20 inactivation in ocular adnexal MALT lymphoma

“…2 To investigate whether A20 inactivation by mutation/deletion leads to enhanced NF-κB activities, we measured the expression of the above NF-κB target genes in 18 cases of OAML with A20 inactivating mutation and 17 cases without any evidence of A20, ABIN-1/2, MALT1 and IGH genetic abnormalities by quantitative RT-PCR. The expression of CCR2, TLR6 and BCL2, although not CD69, was significantly higher in cases with A20 mutation than those without A20 genetic abnormalities (Figure 2).…”

“…1 By analyses of the gene expression profiles, we showed that the NF-κB target genes CCR2, TLR6, BCL2 and CD69 were highly expressed in MALT lymphoma with the above translocations. 2 The above translocations occur frequently in MALT lymphoma of the stomach and lung, but rarely in those of the ocular adnexa, salivary glands and thyroid. 1 By genomic profiling of translocation negative ocular adnexal MALT lymphoma (OAML), we and others identified A20 as the target of 6q23.3 deletion.…”

Lymphoproliferative Disorders of the Gastrointestinal Tract: A Review and Pragmatic Guide to Diagnosis

“…120 The t(11;18)(q21;q21) translocation is restricted to extranodal MALT lymphomas and has not been reported in other forms of marginal zone lymphoma, such as splenic or nodal, or in chronic gastritis associated with H pylori. 121,122 Gastric MALT lymphomas without t(11;18)(q21;q21) often exhibit aneuploidy, for example, trisomy 3, 12, or 18. 118, 119,123 The discovery of t(11;18)(q21;q21) in some patients with gastric MALT lymphoma has led to exciting clinical prognostic correlations.…”