Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.
| Autor: | Hameed KM; School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States., Bollino DR; School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.; Department of Medicine, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States., Shetty AC; Institute of Genome Sciences, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States., Carter-Cooper B; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States., Lapidus RG; School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.; Department of Medicine, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States., Emadi A; School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.; Department of Medicine, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.; Institute of Genome Sciences, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Frontiers in oncology [Front Oncol] 2024 Apr 16; Vol. 14, pp. 1326754. Date of Electronic Publication: 2024 Apr 16 (Print Publication: 2024). |
| DOI: | 10.3389/fonc.2024.1326754 |
| Abstrakt: | Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia -derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR- Cas9 -mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC Competing Interests: AE has received research grants from Jazz Pharmaceuticals, NewLink Genetics, Amgen, and Servier Pharmaceuticals. AE is a global oncology advisory board member for Amgen and has served as an advisory board member for Genentech and Servier. AE and RL are Co-Founders and Scientific Advisors for KinaRx, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Hameed, Bollino, Shetty, Carter-Cooper, Lapidus and Emadi.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|