Molecular Pathogenesis of MALT lymphoma
Hamoudi, Rifat A
University of Cambridge
Department of Pathology
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Hamoudi, R. A. (2010). Molecular Pathogenesis of MALT lymphoma (doctoral thesis).
The original dissertation included a number or articles which were excluded from the digital file for copyright reasons. This is a list of the articles:
1) Hamoudi RA, Appert A, Ye H, Ruskone-Fourmestraux A, Streubel B, Chott A, Raderer M, Gong L, Wlodarska I, De Wolf-Peeters C, MacLennan KA, de Leval L, Isaacson PG, & Du MQ. Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism. Leukemia. 2010 Aug;24(8):1487-1497 http://www.ncbi.nlm.nih.gov/pubmed/20520640
2) Ye H, Gong L, Liu H, Hamoudi RA, Shirali S, Ho L, Chott A, Streubel B, Siebert R, Gesk S, Martin-Subero JI, Radford JA, Banerjee S, Nicholson AG, Ranaldi R, Remstein ED, Gao Z, Zheng J, Isaacson PG, Dogan A & Du MQ. MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol. 2005 Feb;205(3):293-301. http://www.ncbi.nlm.nih.gov/pubmed/15682443
3) Liu H, Hamoudi RA, Ye H, Ruskone-Fourmestraux A, Dogan A, Isaacson PG & Du MQ. t(11;18)(q21;q21) of mucosa-associated lymphoid tissue lymphoma results from illegitimate non-homologous end joining following double strand breaks. Br J Haematol. 2004 May;125(3):318-329. http://www.ncbi.nlm.nih.gov/pubmed/15086412
4) Liu H, Ye H, Ruskone-Fourmestraux A, De Jong D, Pileri S, Thiede C, Lavergne A, Boot H, Caletti G, Wündisch T, Molina T, Taal BG, Elena S, Thomas T, Zinzani PL, Neubauer A, Stolte M, Hamoudi RA, Dogan A, Isaacson PG & Du MQ. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication. Gastroenterology. 2002 May;122(5):1286-1294. http://www.ncbi.nlm.nih.gov/pubmed?term=11984515
5) Liu H, Ye H, Dogan A, Ranaldi R, Hamoudi RA, Bearzi I, Isaacson PG & Du MQ. T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood. 2001 Aug 15;98(4):1182-1187. http://www.ncbi.nlm.nih.gov/pubmed?term=11493468
6) Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, Hamoudi RA, Diss TC, Dogan A, Megraud F, Rambaud JC, Du MQ & Isaacson PG. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet. 2001 Jan 6;357(9249):39-40. http://www.ncbi.nlm.nih.gov/pubmed?term=11197361
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 NF-κB pathway. Gastric MALT lymphomas harbouring such translocation do not respond to Helicobacter pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of MALT lymphoma with and without chromosome translocation, 24 cases (15 translocation-positive and 9 translocation-negative) of MALT lymphomas together with 7 follicular lymphomas and 7 mantle cell lymphomas were analysed by Affymetrix gene expression microarray platform. Unsupervised clustering showed that cases of MALT lymphoma were clustered as a single branch. However, within the MALT lymphoma group, translocation-positive cases were intermingled with translocation-negative cases. Gene set enrichment analysis (GSEA) of the NF-κB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas were characterized by an enhanced expression of NF-κB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and 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. The differential expression of these NF-κB target genes between MALT lymphoma with and without translocation was confirmed by quantitative RT-PCR and immunohistochemistry or Western blot. Expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-κB activation in vitro. In addition, there was cooperation between expression of BCL10, MALT1 or API2-MALT1, and stimulation of the antigen receptor or CD40 or TLR in NF-κB activation as shown by both reporter assay and IκBα degradation. Interestingly, expression of BCL10 but not API2-MALT1 and MALT1, in the presence of LPS stimulation, also triggered IκBβ degradation, suggesting activation of different NF-κB dimers between these oncogenic products. Study by co-immunoprecipitation showed that BCL10 directly interacts with MALT1. Sub-cellular localisation experiments in BJAB B-cells, showed that BCL10 localisation was affected by MALT1. When BCL10 was over-expressed, the protein was predominantly expressed in the nuclei, but when MALT1 was over-expressed, BCL10 was mainly localised in the cytoplasm. When both BCL10 and MALT1 were over-expressed, BCL10 was expressed in the cytoplasm in the early hours when the protein level was low, but in both the cytoplasm and nuclei after 9 hours when the protein level was high. Over-expression of API2-MALT1 did not shown any apparent effect on BCL10 sub-cellular localisation in vitro. Finally, comparison of MALT lymphoma expression microarray with other lymphomas showed lactoferrin to be highly expressed in MALT lymphoma. This was confirmed by qRT-PCR, showing lactoferrin to be significantly over-expressed in MALT lymphoma compared to FL and MCL. Thus lactoferrin may be a potential marker for MALT lymphoma.
Expression microarray, MALT lymphoma, immunohistochemistry, qRT-PCR, bioinformatics, functional analysis, reporter assay, cellular localisation, molecular mechanism, molecular biology
This record's URL: http://www.dspace.cam.ac.uk/handle/1810/238398