| Autor: |
Rondeau, Vincent, Berman, Jacob M., Ling, Tianyi, O'Brien, Cristiana, Culp-Hill, Rachel, Reisz, Julie A., Wunderlich, Mark, Chueh, Yun, Jiménez-Camacho, Karina E., Sexton, Christina, Carter, Katharine M., Stillwell, Cody, St-Germain, Jonathan, Yendi, Duhan, Gupta, Aarushi, Shi, Mary, Bourdine, Aleksandra, Paralkar, Vikram R., Jahangiri, Soheil, Hope, Kristin J. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 9/25/2024, Vol. 16 Issue 766, p1-17, 17p |
| Abstrakt: |
Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry–based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs. However, we do not have a comprehensive understanding of metabolite differences between LSCs and their normal counterparts, hematopoietic stem and progenitor cells (HSPCs). In this study, we used an unbiased mass spectrometry–based metabolomics analysis to define differences in metabolites between primary human LSCs and HSPCs, which revealed that LSCs have a distinct metabolome. Spermidine was the most enriched metabolite in LSCs compared with HSPCs. Pharmacological reduction of spermidine concentrations decreased LSC function but spared normal HSPCs. Polyamine depletion also decreased leukemic burden in patient-derived xenografts. Mechanistically, spermidine depletion induced LSC myeloid differentiation by decreasing eIF5A-dependent protein synthesis, resulting in reduced expression of a select subset of proteins. KAT7, a histone acetyltransferase, was one of the top candidates identified to be down-regulated by spermidine depletion. Overexpression of KAT7 partially rescued polyamine depletion–induced decreased colony-forming ability, demonstrating that loss of KAT7 is an essential part of the mechanism by which spermidine depletion targets AML clonogenic potential. Together, we identified and mechanistically dissected a metabolic vulnerability of LSCs that has the potential to be rapidly translated into clinical trials to improve outcomes for patients with AML. Editor's summary: A major concern for patients with acute myeloid leukemia is relapse after treatment. Leukemic stem cells (LSCs), which reside in the bone marrow and maintain the pool of leukemic cells, are the main culprits behind relapse and thus need to be targeted to prevent relapse from occurring. To identify targetable vulnerabilities of LSCs, Rondeau et al. performed metabolomics profiling of LSCs compared with healthy hematopoietic stem and progenitor cells (HSPCs). They identified the polyamine spermidine as a metabolite specifically enriched in LSCs and then showed that reducing spermidine or total polyamine concentrations could impair LSC function by down-regulating expression of a histone acetyltransferase, KAT7. Polyamine depletion reduced leukemia burden in patient-derived mouse models, suggesting that this could be a therapeutic approach to prevent relapse for patients with AML. —Courtney Malo [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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