Tsingos Erika, Dick Advaita M, Bajoghli Baubak
Computational Developmental Biology Group, Institute of Biodynamics and Biocomplexity, Utrecht University, Utrecht, Netherlands.
Department of Hematology, Oncology, Immunology, and Rheumatology, University, Hospital of Tübingen, Tübingen, Germany.
Elife. 2025 Sep 16;13:RP101137. doi: 10.7554/eLife.101137.
The discovery of genetic alterations in patient samples over the last decades has reinforced a cell-autonomous view of proliferative expansion during T-cell acute lymphoblastic leukemia (T-ALL) development in the thymus. However, the potential contribution of non-cell-autonomous factors, particularly the impact of thymic epithelial cells (TECs) within the thymic niche during the initiation phase, remains unexplored. In this study, we combine a cell-based computational model of the thymus with complementary in vivo experiments in medaka () to systematically analyze the impact of 12 cell-autonomous and non-autonomous factors, individually and in combination, on the proliferation of normal and malignant thymocytes carrying interleukin-7 receptor (IL7R) gain-of-function mutations or elevated IL7R levels, as observed in T-ALL patients. By simulating over 1500 scenarios, we show that while a dense TEC network favored the proliferation of normal thymocytes, it inhibited the proliferation of malignant lineages, which achieved their maximal proliferative capacity when TECs were sparsely distributed. Our in silico model further predicts that specific mutations could accelerate proliferative expansion within a few days. This prediction was experimentally validated, revealing the rapid onset of thymic lymphoma and systemic infiltration of malignant T cells within just 8 days of embryonic development. These findings demonstrate that synergistic interaction between oncogenic alterations and modifications in the thymic niche can significantly accelerate disease progression. Our results also suggest that negative feedback from the proliferative state suppresses thymocyte differentiation. Overall, this multidisciplinary work reveals the critical role of TEC-thymocyte interactions in both the initiation and progression of T-ALL, highlighting the importance of the thymic microenvironment in early leukemogenesis.
在过去几十年中，对患者样本中基因改变的发现强化了一种关于胸腺中T细胞急性淋巴细胞白血病（T-ALL）发展过程中增殖性扩张的细胞自主观点。然而，非细胞自主因素的潜在贡献，特别是胸腺生态位中胸腺上皮细胞（TECs）在起始阶段的影响，仍未得到探索。在本研究中，我们将基于细胞的胸腺计算模型与青鳉体内的补充实验相结合，以系统地分析12种细胞自主和非自主因素单独及组合对携带白细胞介素-7受体（IL7R）功能获得性突变或IL7R水平升高的正常和恶性胸腺细胞增殖的影响，这在T-ALL患者中可见。通过模拟超过1500种情况，我们发现虽然密集的TEC网络有利于正常胸腺细胞的增殖，但它抑制了恶性谱系的增殖，当TECs稀疏分布时，恶性谱系达到其最大增殖能力。我们的计算机模型进一步预测，特定突变可在几天内加速增殖性扩张。这一预测通过实验得到验证，揭示了在胚胎发育仅8天内胸腺淋巴瘤的快速发生以及恶性T细胞的全身浸润。这些发现表明致癌改变与胸腺生态位改变之间的协同相互作用可显著加速疾病进展。我们的结果还表明，增殖状态的负反馈抑制胸腺细胞分化。总体而言，这项多学科研究揭示了TEC-胸腺细胞相互作用在T-ALL起始和进展中的关键作用，突出了胸腺微环境在早期白血病发生中的重要性。
