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Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia
- Source :
- Nature medicine
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.
- Subjects :
- Glutamine
Lymphoblastic Leukemia
T cell
Metabolic reprogramming
Antineoplastic Agents
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Article
General Biochemistry, Genetics and Molecular Biology
law.invention
Mice
03 medical and health sciences
0302 clinical medicine
law
hemic and lymphatic diseases
medicine
Animals
PTEN
Receptor, Notch1
030304 developmental biology
0303 health sciences
biology
General Medicine
3. Good health
medicine.anatomical_structure
Cell metabolism
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer metabolism
embryonic structures
Immunology
cardiovascular system
biology.protein
Suppressor
sense organs
biological phenomena, cell phenomena, and immunity
Subjects
Details
- ISSN :
- 1546170X and 10788956
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Nature Medicine
- Accession number :
- edsair.doi.dedup.....94a334bc65a7eee28a4d3707e5c428d6
- Full Text :
- https://doi.org/10.1038/nm.3955