Acquired resistance to venetoclax plus azacitidine in acute myeloid leukemia : In vitro models and mechanisms
Copyright © 2023 Elsevier Inc. All rights reserved..
The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:216 |
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| Enthalten in: |
Biochemical pharmacology - 216(2023) vom: 15. Okt., Seite 115759 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Carter, Jenna L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 23.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2023.115759 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute myeloid leukemia | |
| 650 | 4 | |a Bax | |
| 650 | 4 | |a Glycolysis | |
| 650 | 4 | |a Mcl-1 | |
| 650 | 4 | |a Pyrimidine metabolism | |
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| 650 | 7 | |a Myeloid Cell Leukemia Sequence 1 Protein |2 NLM | |
| 650 | 7 | |a bcl-2-Associated X Protein |2 NLM | |
| 650 | 7 | |a Azacitidine |2 NLM | |
| 650 | 7 | |a M801H13NRU |2 NLM | |
| 650 | 7 | |a Fatty Acids |2 NLM | |
| 650 | 7 | |a Bridged Bicyclo Compounds, Heterocyclic |2 NLM | |
| 700 | 1 | |a Su, Yongwei |e verfasserin |4 aut | |
| 700 | 1 | |a Qiao, Xinan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jianlei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guan |e verfasserin |4 aut | |
| 700 | 1 | |a Howard, Mackenzie |e verfasserin |4 aut | |
| 700 | 1 | |a Edwards, Holly |e verfasserin |4 aut | |
| 700 | 1 | |a Bao, Xun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Hüttemann, Maik |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jay |e verfasserin |4 aut | |
| 700 | 1 | |a Taub, Jeffrey W |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, Yubin |e verfasserin |4 aut | |
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