Transcriptional analysis of mantle cell lymphoma - a global search for cellular origin and therapeutic targets

This thesis is based upon four original papers describing the characterisation of mantle cell lymphoma (MCL) tumours and cell lines in comparison with different populations of normal B cells. Gene expression profiling, which were used in the studies, has during recent years developed as an important tool in characterisation of different types of malignancies. In this thesis, the technique is used to identify gene signatures in addition to providing information about the mRNA expression of more than 10 000 genes in the samples analysed. We found indications of an antigen-activated origin of MCL, in contrast to the current dogma. De-regulation of apoptosis and proliferation-associated pathways were further identified and possibly therapeutic targets were recognised. In an attempt to define the differences between high and low proliferative MCL, a proliferation-associated signature was established. The genes or gene-products constituting the signature are potential targets for therapy, as the genes are associated with proliferation, which is related to decreased survival time. Furthermore, MCL cell lines were studied to determine their usefulness as in vitro models for MCL. Hierarchical clustering, using a MCL-specific gene list, confirmed that the cell lines had preserved the expression of MCL-associated genes, as they were readily separate from other lymphoma cell lines, primary follicular lymphoma samples and normal B cells. However, one of the MCL-derived cell lines showed less correlation to the primary MCL tumours than the other cell lines. The same cell line carried a mutated VH gene, in contrast to the other MCL cell lines, and may be more suitable as in vitro model for MCL with mutated than unmutated VH genes