Department of Haematology, Christian Medical College, Vellore, India.
Department of Biotechnology, Thiruvalluvar University, Vellore, India.
Leuk Res. 2023 May;128:107054. doi: 10.1016/j.leukres.2023.107054. Epub 2023 Mar 3.
Chemotherapy resistance leading to disease relapse is a significant barrier in treating acute myeloid leukemia (AML). Metabolic adaptations have been shown to contribute to therapy resistance. However, little is known about whether specific therapies cause specific metabolic changes. We established cytarabine-resistant (AraC-R) and Arsenic trioxide-resistant (ATO-R) AML cell lines, displaying distinct cell surface expression and cytogenetic abnormalities. Transcriptomic analysis revealed a significant difference in the expression profiles of ATO-R and AraC-R cells. Geneset enrichment analysis showed AraC-R cells rely on OXPHOS, while ATO-R cells on glycolysis. ATO-R cells were also enriched for stemness gene signatures, whereas AraC-R cells were not. The mito stress and glycolytic stress tests confirmed these findings. The distinct metabolic adaptation of AraC-R cells increased sensitivity to the OXPHOS inhibitor venetoclax. Cytarabine resistance was circumvented in AraC-R cells by combining Ven and AraC. In vivo, ATO-R cells showed increased repopulating potential, leading to aggressive leukemia compared to the parental and AraC-R. Overall, our study shows that different therapies can cause different metabolic changes and that these metabolic dependencies can be used to target chemotherapy-resistant AML.
化疗耐药导致疾病复发是治疗急性髓系白血病（AML）的重大障碍。代谢适应已被证明有助于耐药性的产生。然而，目前还不清楚特定的治疗方法是否会导致特定的代谢变化。我们建立了阿糖胞苷耐药（AraC-R）和三氧化二砷耐药（ATO-R）AML 细胞系，这些细胞系表现出明显的细胞表面表达和细胞遗传学异常。转录组分析显示 ATO-R 和 AraC-R 细胞的表达谱存在显著差异。基因集富集分析显示 AraC-R 细胞依赖 OXPHOS，而 ATO-R 细胞依赖糖酵解。ATO-R 细胞还富集了干性基因特征，而 AraC-R 细胞则没有。线粒体应激和糖酵解应激测试证实了这些发现。AraC-R 细胞的独特代谢适应增加了对 OXPHOS 抑制剂 venetoclax 的敏感性。通过联合使用 Ven 和 AraC，AraC-R 细胞中的阿糖胞苷耐药得到了规避。在体内，ATO-R 细胞显示出增强的再殖能力，导致与亲本细胞和 AraC-R 相比，白血病更具侵袭性。总的来说，我们的研究表明，不同的治疗方法可能会导致不同的代谢变化，并且这些代谢依赖性可用于靶向化疗耐药的 AML。
