Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition
| Autor: | Jan Cools, Inge Lodewijckx, David Nittner, Tom Taghon, Rajeshwar Narlawar, Roger Habets, James Dooley, Adrian Liston, Bart De Strooper, Sofie Demeyer, Delphine Verbeke, Charles E. de Bock, Lutgarde Serneels |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Cell cycle checkpoint T-Lymphocytes Research & Experimental Medicine Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Mice 0302 clinical medicine Conditional gene knockout ADULT PATIENTS Molecular Targeted Therapy 0303 health sciences Receptors Notch Gene targeting General Medicine 3. Good health Leukemia PHASE-I medicine.anatomical_structure Medicine Research & Experimental 030220 oncology & carcinogenesis Gene Targeting Disease Progression GAMMA-SECRETASE INHIBITOR INACTIVATION Signal transduction Life Sciences & Biomedicine Signal Transduction EXPRESSION PRESENILIN-1 T cell Notch signaling pathway 03 medical and health sciences Cell Line Tumor Presenilin-1 medicine Animals Humans TELENCEPHALIN Cell Proliferation 030304 developmental biology Science & Technology MUTATIONS Cell growth business.industry Cell Biology medicine.disease Gastrointestinal Tract MICE Cancer research business RESISTANCE Gene Deletion |
| Zdroj: | Science Translational Medicine. 11 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | Given the high frequency of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of Psen1 in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role. ispartof: SCIENCE TRANSLATIONAL MEDICINE vol:11 issue:494 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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