2026-06-14T05:06:42Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/133412024-11-30T00:36:21Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Xiong, Huizhong author Mancini, Maicol author Gobert, Michael author Shen, Shiqian author Furtado, Glaucia C author Lira, Sergio A author Parkhurst, Christopher N author Garambois, Veronique author Brengues, Muriel author Tadokoro, Carlos E author Trimarchi, Thomas author Gómez-López, Gonzalo author Singh, Amartya author Khiabanian, Hossein author Minuzzo, Sonia author Indraccolo, Stefano author Lobry, Camille author Aifantis, Iannis author Herranz, Daniel author Lafaille, Juan J author Maraver, Antonio author 2021-01-01 The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4+CD8+ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL. Theranostics. 2021 ;11(4):1594-1608. 10.7150/thno.48067 1838-7640 Theranostics 33408769 http://hdl.handle.net/20.500.12105/13341 Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.