Mitochondrial dysfunction fuels drug resistance in adult T-cell acute lymphoblastic leukemia

作者：Shanshan Guo, Ekaterina Bourova-Flin, Sophie Rousseaux, Florent Chuffart, Lijun Peng, Duohui Jing, Jian‐Qing Mi, Saadi Khochbin, Jin Wang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06423-4 · 被引用次数：4 · 研究领域：Cancer, Lipids, and Metabolism、Acute Lymphoblastic Leukemia research、Fatty Acid Research and Health

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive. METHODS: We have built up the largest known T-ALL tumor bank, with a median follow-up of 32 months, including our transcriptomic data from 79 newly sequenced tumors that adds to the 54 publicly accessible samples. Computational analyses and a series of functional assays were performed to investigate the molecular links between altered mitochondrial activity and drug resistance. RESULTS: The transcriptomic analysis revealed that down-regulation of mitochondrial activity is a potent driver of ABCB1 activation, a gene strongly associated with multidrug resistance. In tumors with low mitochondrial activity, the impaired fatty acids β-oxidation leads to intracellular lipid accumulation, which is directly involved in ABCB1 activation. Indeed, our data show that lipid neo-synthesis and accumulation promotes the activation of lipogenic transcription factors, liver X receptors (LXRs), which act as drivers of ABCB1 expression. Tumor data analyses confirmed that high ABCB1 expression in tumour samples is indeed...