Recent discoveries of ZAP-70 (ζ chain–associated protein kinase of 70 kD) and Syk (spleen tyrosine kinase) inhibitors (gefitinib1 and fostamatinib2 respectively) provide promising therapeutic options for patients with chronic lymphocytic leukemia (CLL). However, the precise action of these inhibitors in the B cell receptor (BCR) signaling pathway is not well understood. This study designs an integrated mechanistic description of the BCR signaling pathway in CLL cells, and investigates the effects of possible inhibitors on this pathway. In this work, we examined several computational models of ZAP-70 and Syk regulation in the BCR signaling pathway to explain the observed differences in the clinical behaviors of ZAP+ / ZAP- phenotypes of B-CLL patients. Specifically, we characterized the effects of different ZAP-70 and Syk expression and phosphorylation levels on the BCR activation threshold. The correlations between the observed and calculated trends are reproduced quantitatively.
Our calculations show that depending on the amount of Syk that is expressed in cells, increased ZAP-70 expression is correlated with decreased levels of phosphorylated ZAP-70 and Syk, and vice versa. ZAP-70 and Syk phosphorylation occur independently, but is dependent on the amount of ZAP-70 and Syk that is expressed in cells. These results support reported experimental observations.3 We also find that ZAP-70 is able to compensate for a missing Syk functionality with an increased BCR activation threshold in Syk-deficient B-CLL cells, similar to Syk-deficient B cell study.4 In addition, we find that selective inhibition of either Syk or ZAP-70 will result in a disease relapse. This suggests the used of two inhibitors rather than one for the treatment of ZAP-70+ patients, based on our model. Lastly, we find that enhanced or reduced BCR signaling is observed at low amounts of Syk expression in CLL cells. However, this computational prediction needs to be verified experimentally in order to identify a viable physiological range of the amount of Syk that is expressed in B-CLL cells for ZAP-70+ and ZAP-70- phenotypes.
Our results uncover molecular mechanisms of ZAP-70 and Syk regulation in the BCR signaling pathway for its future therapeutic use in B-CLL. Our in silico network analysis will help in the development of immunotherapies targeting ZAP-70 and Syk functions to regulate B-CLL responses. Furthermore, our study provides information about responses to certain cancer therapies, and tumor progression.
1 Dielschneider, R. F. et al. Cell Death Dis. 2014, 5 (10), e1439.
2 Friedberg, J. W. et al. Blood 2010, 115 (13), 2578.
3 Kaplan, D. et al. Cytometry B Clin. Cytom. 2010, 78 (2), 115.
4 Kong, G. H. et al. Immunity 1995, 2 (5), 485.
Citation Format: Maria P. Frushicheva, Arup K. Chakraborty. In silico models for B cell receptor signaling in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B039.
- ©2016 American Association for Cancer Research.