Identificación del gen MALT1 como oncogén dominante en el linfoma MALT.

Résumé

Characteristic primary translocations in non-Hodgkin lymphomas (NHL-B), trigger deregulation of a proto-oncogene (most of them mediated by rearrangement with IGH gene) and thus, generating changes in the expression of cells with neoplastic potential. Another frequent genetic lesions are the chromosomic deletions inactivating tumour supressor genes as p53 ó p16. These rearrangements together with primary translocations are asumed to be related to tumoral progression and transformation. Genetic amplification is another frequent mechanism of rearrangement in NHL-B (oncogenes like REL, c-MYC, or BCL2). Fluorescent in situ hybridisation (FISH) is related to cytogenetics and molecular biology and represents the link between an specific rearrangement at the chromosome level and the genomic candidate region, allowing detection of the genes affected. This thesis includes three papers with the follow objective: the detection and characterisation of specific molecular rearrangements of NHL-B subtypes. Flanking probes detecting all possible translocations of BCL6 are developed in the first paper. The gene is rearranged in about 40% of diffuse large B cell lymphoma but prognosis value is still controversial. In the second paper, specific rearrangements detected in splenic marginal zone lymphoma are possible specific regions related to progression or agressive disease: trisomy +3 and rearrangements in chromosomal locations 19p13 and 7p22-q22. Two cases of MALT lymphoma showing t(14;18) have been characterised in the third paper, allowing us the molecular cloning of a novel translocation affecting MALT1 gene, a paracaspase involved in the immune response and proliferation mediated by NF-kB. We also demonstrate that the gene is amplified in several cell lines derived from NHL-B. Both amplification and translocation induce increase of MALT1 expression.