Dynamical and Structural Analysis of a T Cell Survival Network Identifies Novel Candidate Therapeutic Targets for Large Granular Lymphocyte Leukemia

Abstract

The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-LGL states of 54 components of the network, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions. We further test and validate one of these newly identified states experimentally. Specifically, we verify the prediction that the node SMAD is over-active in leukemic T-LGL by demonstrating the predominant phosphorylation of the SMAD family members Smad2 and Smad3. Our systematic perturbation analysis using dynamical and structural methods leads to the identification of 19 potential therapeutic targets, 68% of which are corroborated by experimental evidence. The novel therapeutic targets provide valuable guidance for wet-bench experiments. In addition, we successfully identify two new candidates for engineering long-lived T cells necessary for the delivery of virus and cancer vaccines. Overall, this study provides a bird's-eye-view of the avenues available for identification of therapeutic targets for similar diseases through perturbation of the underlying signal transduction network.

Author Summary

T-LGL leukemia is a blood cancer characterized by an abnormal increase in the abundance of a type of white blood cell called T cell. Since there is no known curative therapy for this disease, identification of potential therapeutic targets is of utmost importance. Experimental identification of manipulations capable of reversing the disease condition is usually a long, arduous process. Mathematical modeling can aid this process by identifying potential therapeutic interventions. In this work, we carry out a systematic analysis of a network model of T cell survival in T-LGL leukemia to get a deeper insight into the unknown facets of the disease. We identify the T-LGL status of 54 components of the system, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions, one of which we validate by follow-up experiments. By deciphering the structure and dynamics of the underlying network, we identify component perturbations that lead to programmed cell death, thereby suggesting several novel candidate therapeutic targets for future experiments.