Guo Shanshan, Bourova-Flin Ekaterina, Rousseaux Sophie, Chuffart Florent, Peng Lijun, Jing Duohui, Mi Jian-Qing, Khochbin Saadi, Wang Jin
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Univ. Grenoble Alpes, CNRS UMR 5309 and INSERM U1209, Institute for Advanced Biosciences, 38706, La Tronche, France.
J Transl Med. 2025 May 14;23(1):542. doi: 10.1186/s12967-025-06423-4.
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 associated with reduced mitochondrial gene expression, lipid droplet enrichment, increased tumour aggressiveness, and significantly shorter patient survival. CONCLUSIONS: Our study demonstrates that reduced mitochondrial activity drives multidrug resistance in adult T-ALL via lipid-mediated activation of ABCB1. These findings enhance our understanding of the biology of aggressive T-ALL and provide insight into mechanisms of resistance to conventional chemotherapy. Consequently, we propose that targeting de novo lipogenesis and restricting dietary fats, such as caprylic acid, may help overcome treatment resistance in patients with T-ALL exhibiting low mitochondrial activity. TRIAL REGISTRATION: The clinical trial was registered under the identifiers ChiCTR-ONRC-14004968 and ChiCTR2000031553 at ClinicalTrials.gov.
背景：T细胞急性淋巴细胞白血病（T-ALL）是一种相对罕见的血液系统恶性肿瘤，其特征为未成熟T淋巴母细胞的不受控制增殖，且通常预后不良。我们之前的研究表明，线粒体活性降低与T-ALL肿瘤的侵袭性相关。然而，这一现象背后的机制及其对治疗耐药性的影响在很大程度上仍不清楚。 方法：我们建立了已知最大的T-ALL肿瘤库，中位随访时间为32个月，其中包括来自79个新测序肿瘤的转录组数据，以及另外54个可公开获取的样本。通过计算分析和一系列功能试验来研究线粒体活性改变与耐药性之间的分子联系。 结果：转录组分析显示，线粒体活性下调是ABCB1激活的一个有力驱动因素，ABCB1是一个与多药耐药密切相关的基因。在线粒体活性低的肿瘤中，脂肪酸β-氧化受损导致细胞内脂质积累，这直接参与了ABCB1的激活。实际上，我们的数据表明脂质的从头合成和积累促进了生脂转录因子肝脏X受体（LXRs）的激活，而LXRs是ABCB1表达的驱动因素。肿瘤数据分析证实，肿瘤样本中ABCB1的高表达确实与线粒体基因表达降低、脂滴富集、肿瘤侵袭性增加以及患者生存期显著缩短相关。 结论：我们的研究表明，线粒体活性降低通过脂质介导的ABCB1激活导致成人T-ALL的多药耐药。这些发现加深了我们对侵袭性T-ALL生物学特性的理解，并为传统化疗耐药机制提供了见解。因此，我们建议靶向从头脂肪生成并限制饮食中的脂肪，如辛酸，可能有助于克服线粒体活性低的T-ALL患者的治疗耐药性。 试验注册：该临床试验已在ClinicalTrials.gov上以标识符ChiCTR-ONRC-14004968和ChiCTR2000031553进行注册。
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