| Added by | celine.gongora |
|---|---|
| Group name | EquipeCG |
| Item Type | Journal Article |
| Title | Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia |
| Creator | Xiong et al. |
| Author | Huizhong Xiong |
| Author | Maicol Mancini |
| Author | Michael Gobert |
| Author | Shiqian Shen |
| Author | Glaucia C. Furtado |
| Author | Sergio A. Lira |
| Author | Christopher N. Parkhurst |
| Author | Muriel Brengues |
| Author | Carlos E. Tadokoro |
| Author | Thomas Trimarchi |
| Author | Amartya Singh |
| Author | Hossein Khiabanian |
| Author | Sonia Minuzzo |
| Author | Stefano Indraccolo |
| Author | Camille Lobry |
| Author | Iannis Aifantis |
| Author | Daniel Herranz |
| Author | Juan J. Lafaille |
| Author | Antonio Maraver |
| Abstract | 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 ?-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. |
| Publication | Theranostics |
| Volume | 11 |
| Issue | 4 |
| Pages | 1594-1608 |
| Date | 2021 |
| Journal Abbr | Theranostics |
| Language | eng |
| DOI | 10.7150/thno.48067 |
| ISSN | 1838-7640 |
| Library Catalog | PubMed |
| Extra | PMID: 33408769 PMCID: PMC7778594 |
| Tags | Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Biomarkers, Tumor, Calcium-Binding Proteins, Cell Proliferation, demcizumab, DLL4, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Notch pathway, original, patient-derived xenografts, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Notch, Spleen, T-ALL, Tumor Cells, Cultured, Xenograft Model Antitumor Assays |
| Date Added | 2022/08/29 - 15:39:20 |
| Date Modified | 2022/08/29 - 16:26:32 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
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