A System-Level Study Reveals That a Defective Thymic Niche Accelerates the T-ALL Initiation

Abstract

The ontogeny of T-cell acute lymphoblastic leukemia (T-ALL) is unknown. In humans and mice, T-ALL is diagnosed when malignant T cells are detectable in the peripheral blood, i.e., at a stage when disease development is complete. Therefore, the malignant processes in the thymus - where the T cells develop - are an unexplored "black box". We took an interdisciplinary approach combining in vivo experiments with computational modeling to investigate the role of the thymic niche in disease manifestation. We focused on the role of interleukin 7 (IL-7) in the thymus, as approximately 70-80% of T-ALL patients have either increased IL-7 receptor (IL-7R) expression or gain-of-function mutations in this gene. In addition, autocrine production of IL-7 by T-ALL blasts has been detected in some patients. Using our recently developed "virtual thymus" model (Aghaallaei et al., Science Advances, 2021), we first simulated more than 200 scenarios to find out the conditions that lead to massive expansion of a single clone in the thymus. We then genetically engineered thymocytes and thymic epithelial cells (TECs) in medaka fish based on in silico predictions. Consistent with our computational model, we found that manipulation of thymocytes or TECs alone resulted in only 25% (N=36) and 10% (N=29) T-ALL development, respectively, in the thymus of Medaka larvae after five days; however, this frequency was accelerated to 54% (N=45) when both cell types were manipulated simultaneously. Our results strongly suggest that defective thymic niche has a strong impact on T-ALL development. Taken together, we propose a previously unknown mechanism that may trigger T-ALL initiation in the thymus. In addition, we introduce the "virtual thymus" as a new versatile in silico model that can predict the outcome of conditions for the development or treatment of T-ALL.