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

María Rodríguez Martínez, Alberto Corradin, Ulf Klein, Mariano Javier Álvarez, Gianna M. Toffolo, Barbara Di Camillo, Andrea Califano, Gustavo A. Stolovitzky

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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. 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.

Original languageEnglish
Pages (from-to)2672-2677
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number7
DOIs
StatePublished - 14 Feb 2012
Externally publishedYes

Keywords

  • B cell differentiation
  • Gene regulatory networks
  • Immunity
  • Master regulators

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