Quantitative modeling of the terminal differentiation of B cells and mechanisms of lymphomagenesis.
Proc Natl Acad Sci U S A
; 109(7): 2672-7, 2012 Feb 14.
Article
em En
| MEDLINE
| ID: mdl-22308355
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
/
Diferenciação Celular
/
Linfoma
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2012
Tipo de documento:
Article