PB1703: MODELING T-CELL DEVELOPMENT AND T-ALL INITIATION

HemaSphere, vol. 7, pp. e25600fc

Abstract

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy derived from abnormal developing T-cells (thymocytes) within the thymus. 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. Thus far, the ontogeny of T-ALL is unknown. Therefore, we are modeling T-cell development and disease onset. Aims: We aim to get a deeper understanding of T-ALL initiation and progression. Methods: We used an interdisciplinary approach to address this issue: First, we took advantage of our recently developed “virtual thymus”, a computational model of thymus organ (Aghaallaei et al., Science Advances, 2021), and simulated conditions in which either the level of cytokine interleukin (IL-7) by thymic epithelial cells (TECs) or its receptor on a thymocyte was upregulated. Additionally, we introduced a dominant active interleukin 7 receptor (IL-7R) mutation. The outcome of simulations was then tested with our animal model system by genetically engineered thymocytes and TECs. Results: In an unbiased strategy, we simulated >300 different conditions and selected scenarios that resulted in clonal expansion. Consistent with in silico analysis, our in vivo model showed that manipulation of thymocytes, either by IL-7, IL-7R or Notch1 upregulation, resulted in thymoma formation within less than 3 days only in 10%, 25% or 30% of cases, respectively. However, this frequency was accelerated to 80% when both the dominant active IL-7R level and Notch were upregulated. Summary/Conclusion: We offer new insights in the mechanism that may trigger T-ALL initiation in the thymus. In addition, we show the “virtual thymus” as a new functional in silico model to predict the outcome of various conditions for the T-cell and T-ALL development or treatment. Keywords: T-ALL, In vivo imaging, Animal model, Thymus

Authors 5

1. Advaita M Dick

   Universitätsklinikum Tübingen

   Affiliation as printed

   Universityhospital Tübingen, Germany, Translational Oncology, internal Medicine 2, Tübingen, Germany

2. Erika Tsingos Aachen Institute of Mathematics, University Leiden

   Leiden University

   Affiliation as printed

   Institute of Mathematics, University Leiden, Netherlands, Leiden, The Netherlands

3. Narges Aghaallaei

   Universitätsklinikum Tübingen

   Affiliation as printed

   Universityhospital Tübingen, Germany, Translational Oncology, internal Medicine 2, Tübingen, Germany

4. Julia Skokowa

   Universitätsklinikum Tübingen

   Affiliation as printed

   Universityhospital Tübingen, Germany, Translational Oncology, internal Medicine 2, Tübingen, Germany

5. Baubak Bajoghli

   Universitätsklinikum Tübingen

   Affiliation as printed

   Universityhospital Tübingen, Germany, Translational Oncology, internal Medicine 2, Tübingen, Germany