Quantitative modeling of the terminal differentiation of B cells and mechanisms of lymphomagenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 7; pp. 2672 - 2677
• Main Authors: Martínez, María Rodríguez, Corradin, Alberto, Klein, Ulf, Álvarez, Mariano Javier, Toffolo, Gianna M, di Camillo, Barbara, Califano, Andrea, Stolovitzky, Gustavo A
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.02.2012; National Acad Sciences
• Subjects: antigens; B cell lymphoma; B lymphocytes; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Bcl-6 protein; Biological Sciences; Biosynthesis; Cell Differentiation; Cellular differentiation; Data processing; Differentiation; Feedback; Gene expression; Gene Expression Profiling; Genetic mutation; Genetics; Germinal centers; Humans; Hysteresis; Immunologic Memory; Immunological memory; Interferon regulatory factor 4; Kinetics; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma - genetics; Lymphoma - pathology; Memory cells; Modeling; Parametric models; Pathology; Physiology; Plasma cells; regulator genes; T cell lymphoma; T lymphocytes; Transcription
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1113019109

Mature B-cell exit from germinal centers is controlled by a transcriptional regulatory module that integrates antigen and T-cell signals and, ultimately, leads to terminal differentiation into memory B cells or plasma cells. Despite a compact structure, the module dynamics are highly complex because of the presence of several feedback loops and self-regulatory interactions, and understanding its dysregulation, frequently associated with lymphomagenesis, requires robust dynamical modeling techniques. We present a quantitative kinetic model of three key gene regulators, BCL6, IRF4, and BLIMP, and use gene expression profile data from mature human B cells to determine appropriate model parameters. The model predicts the existence of two different hysteresis cycles that direct B cells through an irreversible transition toward a differentiated cellular state. By synthetically perturbing the interactions in this network, we can elucidate known mechanisms of lymphomagenesis and suggest candidate tumorigenic alterations, indicating that the model is a valuable quantitative tool to simulate B-cell exit from the germinal center under a variety of physiological and pathological conditions.