Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/13341
Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.
Xiong, Huizhong | Mancini, Maicol | Gobert, Michael | Shen, Shiqian | Furtado, Glaucia C | Lira, Sergio A | Parkhurst, Christopher N | Garambois, Veronique | Brengues, Muriel | Tadokoro, Carlos E | Trimarchi, Thomas | Gómez-López, Gonzalo CNIO | Singh, Amartya | Khiabanian, Hossein | Minuzzo, Sonia | Indraccolo, Stefano | Lobry, Camille | Aifantis, Iannis | Herranz, Daniel | Lafaille, Juan J | Maraver, Antonio
Theranostics. 2021 ;11(4):1594-1608.
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.
Gene Expression Regulation, Neoplastic | Adaptor Proteins, Signal Transducing | Animals | Apoptosis | Biomarkers, Tumor | Calcium-Binding Proteins | Cell Proliferation | Female | Humans | Mice | Mice, Inbred NOD | Mice, SCID | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma | Receptors, Notch | Spleen | Tumor Cells, Cultured | Xenograft Model Antitumor Assays