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Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia.
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- Additional Information
- Source:
Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
- Publication Information:
Publication: New York Ny : Nature Publishing Company
Original Publication: New York, NY : Nature Pub. Co., [1995-
- Subject Terms:
- 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.
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- Grant Information:
R01 MH117128 United States MH NIMH NIH HHS; R01 CA129382 United States CA NCI NIH HHS; CA120196 United States CA NCI NIH HHS; R01CA129382 United States CA NCI NIH HHS; R01 CA120196 United States CA NCI NIH HHS
- Accession Number:
0 (Antineoplastic Agents)
0 (Notch1 protein, mouse)
0 (Receptor, Notch1)
0RH81L854J (Glutamine)
- Publication Date:
Date Created: 20150922 Date Completed: 20160119 Latest Revision: 20220331
- Publication Date:
20240829
- Accession Number:
PMC4598309
- Accession Number:
10.1038/nm.3955
- Accession Number:
26390244
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