دورية أكاديمية
Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity
| العنوان: | Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity |
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| المؤلفون: | Cristiana O’Brien, Tianyi Ling, Jacob M. Berman, Rachel Culp-Hill, Julie A. Reisz, Vincent Rondeau, Soheil Jahangiri, Jonathan St-Germain, Vinitha Macwan, Audrey Astori, Andy Zeng, Jun Young Hong, Meng Li, Min Yang, Sadhan Jana, Fabia Gamboni, Emily Tsao, Weiyi Liu, John E. Dick, Hening Lin, Ari Melnick, Anastasia Tikhonova, Andrea Arruda, Mark D. Minden, Brian Raught, Angelo D'Alessandro, Courtney L. Jones |
| المصدر: | Haematologica, Vol 108, Iss 9 (2023) |
| بيانات النشر: | Ferrata Storti Foundation, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs |
| مصطلحات موضوعية: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| الوصف: | Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease-initiating leukemia stem cells (LSC). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSC. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSC. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSC but is not essential for normal human hematopoietic stem and progenitor cell function. In order to elucidate the molecular mechanisms by which SIRT3 is essential in LSC we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support OXPHOS and ATP production in human LSC. Further, we discovered two approaches to further sensitize LSC to SIRT3 inhibition. First, we found that LSC tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSC to YC8-02 and potentiates LSC death. Second, SIRT3 inhibition sensitizes LSC to the BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/11038; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2022.281894 |
| URL الوصول: | https://doaj.org/article/365041b041f04292a5cd13ba5d068c3d |
| رقم الأكسشن: | edsdoj.365041b041f04292a5cd13ba5d068c3d |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2022.281894 |