Differential gene expression analysis, using high-density microarray chips, demonstrated 300-400 genes to be deregulated in mantle cell lymphomas (MCLs) compared with normal B-cell populations. To investigate the significance of this genetic signature in lymphoma etiology and diagnostics, we selected 90 annotated genes involved in a number of cellular functions for further analysis. Our findings demonstrated a normal gene expression of CCR7, which indicated a normal homing to primary follicles, which was in contrast to other receptors for B-cell trafficking, such as a significant down-regulation for CXCR5 and CCR6, as well as down-regulation of IL4R involved in differentiation. This indicated that the malignant transformation of a normal B cell could have appeared during the transition of a primary follicle to a germinal center, i.e., after an initial B-cell activation. Genes involved in blockage of antiproliferative signals in normal cells were also deregulated, e.g., gene expression of TGF beta 2 and Smad3 was suppressed in MCLs. Furthermore, lymphoproliferative signal pathways were active in MCLs compared with normal B cells, because genes encoding, e.g., IL10R alpha and IL18 were up-regulated, as were oncogenes like Bcl-2 and MERTK. Genes encoding receptors for different neurotransmitters mediating B-cell stimulation, such as norepinephrine and cannabinoids were also up-regulated, again illustrating deregulation of a complex network of genes involved in growth and differentiation. Furthermore, hierarchical cluster analysis revealed two subpopulations of MCLs, which indicates that despite the homogeneous and strong overexpression of cyclin D1, further subtyping might be possible.