Abstract A24: ZAP-70 and SYK regulation in the B cell receptor pathway in chronic lymphocytic leukemia

Abstract

Abstract Recent discoveries of inhibitors for Syk (spleen tyrosine kinase) family protein kinases provide promising therapeutic options for patients with chronic lymphocytic leukemia (CLL). However, molecular mechanisms of these inhibitors in the B cell receptor (BCR) signaling pathway are not well understood. This study investigates functionality of Syk family protein kinases and their inhibitors in the BCR signaling pathway in CLL cells. In this work, we tested several computational models of ZAP-70 (ζ chain–associated protein kinase of 70 kD) and SYK regulation in the BCR signaling pathway to explain the observed differences in the clinical behaviors of ZAP-70+ / ZAP-70- phenotypes of CLL patients. Specifically, we characterized the effects of different ZAP-70 and SYK expression and phosphorylation levels on the BCR activation threshold. Using stochastic simulations of BCR signaling network, we reproduced the correlations between the observed and calculated trends quantitatively. We find that an increased ZAP-70 expression is correlated with decreased levels of phosphorylated ZAP-70 and SYK, depending on the amount of SYK that is expressed in cells. Our calculations also show 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 cells. Furthermore, our computational model predicts a dual inhibition of ZAP-70 and SYK for the treatment of ZAP-70+ patients, as a selective inhibition of either ZAP-70 or SYK results in disease relapse. Our findings uncover molecular mechanisms of ZAP-70 and SYK regulation in the BCR signaling pathway for the development of CLL immunotherapies. Citation Format: Maria P. Frushicheva. ZAP-70 and SYK regulation in the B cell receptor pathway in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A24.