Mathematical modelling of the role of GADD45β in the pathogenesis of multiple myeloma

Abstract

Multiple myeloma (MM) is an incurable disease with relatively high morbidity and mortality rates. Great efforts were made to develop nuclear factor-kappa B (NF-κB)-targeted therapies against MM disease. However, these treatments influence MM cells as well as normal cells, inevitably causing serious side effects. Further research showed that NF-κB signalling promotes the survival of MM cells by interacting with JNK signalling through growth arrest and DNA damage-inducible beta (GADD45β), the downstream module of NF-κB signalling. The GADD45β-targeted intervention was suggested to be an effective and MM cell-specific treatment. However, the underlying mechanism through which GADD45β promotes the survival of MM cells is usually ignored in the previous models. A mathematical model of MM is built in this paper to investigate how NF-κB signalling acts along with JNK signalling through GADD45β and MKK7 to promote the survival of MM cells. The model cannot only mimic the variations in bone cells, the bone volume and MM cells with time, but it can also examine how the NF-κB pathway acts with the JNK pathway to promote the development of MM cells. In addition, the model also investigates the efficacies of GADD45β- and NF-κB-targeted treatments, suggesting that GADD45β-targeted therapy is more effective but has no apparent side effects. The simulation results match the experimental observations. It is anticipated that this model could be employed as a useful tool to initially investigate and even explore potential therapies involving the NF-κB and JNK pathways in the future.

Keywords

• mathematical model
• multiple myeloma
• gadd45β|mkk7 complex
• the nf-κb pathway