2. Academic Validation
  3. Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition

Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition

  • Sci Transl Med. 2019 May 29;11(494):eaau6246. doi: 10.1126/scitranslmed.aau6246.
Roger A Habets 1 2,  Charles E de Bock 3 4 5,  Lutgarde Serneels 1 2,  Inge Lodewijckx 3 4,  Delphine Verbeke 3 4,  David Nittner 6 7,  Rajeshwar Narlawar 1 2,  Sofie Demeyer 3 4,  James Dooley 2 8,  Adrian Liston 2 8,  Tom Taghon 9 10,  Jan Cools 11 4,  Bart de Strooper 12 2 13
Affiliations

Affiliations

  • 1 Department of Neurosciences, Leuven Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium.
  • 2 VIB Center for Brain and Disease Research, VIB, 3000 Leuven, Belgium.
  • 3 Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
  • 4 VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium.
  • 5 Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia.
  • 6 Histopathology Expertise Center, VIB-KU Leuven Center for Cancer Biology, 3000 Leuven, Belgium.
  • 7 Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
  • 8 Department of Microbiology and Immunology, KU Leuven, 3000 Leuven, Belgium.
  • 9 Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
  • 10 Cancer Research Institute Ghent, 9000 Ghent, Belgium.
  • 11 Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium. bart.destrooper@kuleuven.vib.be jan.cools@kuleuven.vib.be.
  • 12 Department of Neurosciences, Leuven Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium. bart.destrooper@kuleuven.vib.be jan.cools@kuleuven.vib.be.
  • 13 Dementia Research Institute, University College London, London WC1E 6BT, UK.
PMID: 31142678 DOI: 10.1126/scitranslmed.aau6246
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.

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