Temporal genetic program following B-cell receptor cross-linking: altered balance between proliferation and death in healthy and malignant B cells

Gene expression in cells is a dynamic process but is usually examined at a single time point. We used gene expression profiling over time to build temporal models of gene transcription after B-cell receptor (BCR) signaling in healthy and malignant B cells and chose this as a model since BCR cross-linking induces both cell proliferation and apoptosis, with increased apoptosis in chronic lymphocytic leukemia (CLL) compared to healthy B cells. To determine the basis for this, we examined the global temporal gene expression profile for BCR stimulation and developed a linear combination method to summarize the effect of BCR simulation over all the time points for all patients. Functional learning identified common early events in healthy B cells and CLL cells. Although healthy and malignant B cells share a common genetic pattern early after BCR signaling, a specific genetic program is engaged by the malignant cells at later time points after BCR stimulation. These findings identify the molecular basis for the different functional consequences of BCR cross-linking in healthy and malignant B cells. Analysis of gene expression profiling over time may be used to identify genes that might be rational targets to perturb these pathways.