期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 7, 页码 2672-2677出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1113019109
关键词
B cell differentiation; gene regulatory networks; immunity; master regulators
资金
- National Cancer Institute [1R01CA109755-01A1]
- National Institute of Allergy and Infectious Diseases [1R01AI066116-01]
- National Institutes of Health [1U54CA121852-01A1, 2U54CA121852-06]
Mature B-cell exit fromgerminal 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. Wepresent 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.
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