To discover new essential regulatory pathways in B lymphoma cells a combined analysis of experimental and clinical high throughput data was performed. Among others, a specific cluster of coherently expressed genes named BCR.1 was identified in primary lymphoma samples. These coherently expressed genes are suppressed by -IgM treatement of lymphoma cells in vitro. This B cell receptor activation leads to a G2 phase prolongation, delayed entry into the M phase, an overall diminished capacity of the cells to enter into mitosis and defects in metaphases. Cytogenetic changes are detected under long term -IgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc coregulated genes in distinct groups of lymphoma patients is observed. In addition to the impact of c-Myc in the regulation of cell cycle regulators, BCR.1 genes are regulated by a combined action of IKK2, MAPK14 and JNK. Finally, the BCR.1 index discriminates activated B cell like and germinal centre B cell like diffuse large B cell lymphoma. Therefore, a new regulatory circuit is described affecting cell cycle and chromosome instability in B cells.