control of humoral immune responses. It would be interesting to investigate whether their e pression is functionally linked to the recently observed aberrations in CD58 or 2M in DLBCLs that might be involved in differences in the capacity to escape host immune responses. RGS1 gene e pression is characteristic for GCB like DLBCLs. It is part of the IgM driven gene module. RGS1 affects chemokine receptor signalling contributing to its desensitization. However, the role of chemo kine signalling in lymphomagenesis is not yet fully understood. There are reports suggesting that NHLs e press functional chemokine receptors. These, at least in part, dictate tissue localisation and perhaps metastatic potential. However, other reports show that DLBCLs are less sensitive for the C CR4 ligands C CL12 and 13.

The gene e pression changes described above for CCR7 and C CL10 suggest a strong difference of DLBCLs regarding migratory potential and recruitment capacity of cells of the microenvironment but also spe cific chemokine responsiveness. Because CCR7 and Drug_discovery C CL10 play a pivotal role in the homing of tumour cells as shown by its role in chronic lymphatic leukemia or Hodgkin lymphoma this has to be investigated in the future in more detail. It would be interesting to estimate its role in differences in lymphoma dissemination in re lation to the clinical outcome. Strikingly, gene modules of IL21, CD40L or IgM, even though derived from different data sets, almost per fectly discriminate individual DLBCL. The higher a lymphoma e presses direct IgM targets the higher it also e presses IL21 or CD40L inducible genes and vice versa.

While some e planations can be taken into ac count, we would favour the following the aperture of global gene e pression changes obtained by computa tional biology is condensing pathway activities and sup ports the idea of parallel or equivalent functioning oncogenic activities in individual DLBCLs. We wanted to further e plore potential regulatory mechanisms driving differential e pression of gene mod ules. In order to define potential key molecular determi nants, signalling pathways involved in the regulation of a set of genes affected by in vitro interventions were spe cially inhibited using chemical inhibitors.

B cell receptor regulated genes are dominantly affected by ERK1 2 and PI3K activation Pathway activation by IL21, CD40L, IgM, BAFF or LPS reflects qualitative and quantitative differences mediated by the activation of the following pathways Jak STAT, NF ��B, JNK1 2, p38a, PI3K, Erk1 2 and Ca2 influ by immunoblotting, kinase activity measurement or flow cytometry. We summar ized the pathways activated in our model system in a scheme on Figure 6A. IgM treatment is associated with Ca2 mobilization. Furthermore Erk1 2, Akt and p38a phosphorylation or enhanced activity of JNK is observed. In addition, the canonical and non canonical NF��B pathways are activated to some e tent as revealed by I��B degradation and p100 to p52 processing. CD