1. Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition
- Author
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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, and Lutgarde Serneels
- Subjects
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 - Abstract
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
- Published
- 2019
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