Targeting sphingolipid metabolism in chronic lymphocytic leukemia.

IF 3.2 4区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Flora Nguyen Van Long, Trang Le, Patrick Caron, Délya Valcourt-Gendron, Roxanne Sergerie, Isabelle Laverdière, Katrina Vanura, Chantal Guillemette
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Abstract

Elevated levels of circulating C16:0 glucosylceramides (GluCer) and increased mRNA expression of UDP-glucose ceramide glycosyltransferase (UGCG), the enzyme responsible for converting ceramides (Cer) to GluCer, represent unfavorable prognostic markers in chronic lymphocytic leukemia (CLL) patients. To evaluate the therapeutic potential of inhibiting GluCer synthesis, we genetically repressed the UGCG pathway using in vitro models of leukemic B cells, in addition to UGCG pharmacological inhibition with approved drugs such as eliglustat and ibiglustat, both individually and in combination with ibrutinib, assessed in cell models and primary CLL patient cells. Cell viability, apoptosis, and proliferation were evaluated in vitro, and survival and apoptosis were examined ex vivo. UGCG inhibition efficacy was confirmed by quantifying intracellular sphingolipid levels through targeted lipidomics using mass spectrometry. Other inhibitors of sphingolipid biosynthesis pathways were similarly assessed. Blocking UGCG significantly decreased cell viability and proliferation, highlighting the oncogenic role of UGCG in CLL. The efficient inhibition of UGCG was confirmed by a significant reduction in GluCer intracellular levels. The combination of UGCG inhibitors with ibrutinib demonstrated synergistic effect. Inhibitors that target alternative pathways within sphingolipid metabolism, like sphingosine kinases inhibitor SKI-II, also demonstrated promising therapeutic effects both alone and when used in combination with ibrutinib, reinforcing the oncogenic impact of sphingolipids in CLL cells. Targeting sphingolipid metabolism, especially the UGCG pathway, represents a promising therapeutic strategy and as a combination therapy for potential treatment of CLL patients, warranting further investigation.

Abstract Image

针对慢性淋巴细胞白血病的鞘脂代谢。
慢性淋巴细胞白血病(CLL)患者循环中C16:0葡萄糖基甘油三酯(GluCer)水平的升高和负责将神经酰胺(Cer)转化为GluCer的酶--UDP-葡萄糖神经酰胺糖基转移酶(UGCG)mRNA表达的增加是不利的预后指标。为了评估抑制 GluCer 合成的治疗潜力,我们利用白血病 B 细胞的体外模型对 UGCG 通路进行了基因抑制,此外还利用已获批准的药物(如 eliglustat 和 ibiglustat)对 UGCG 进行了药理抑制。在体外评估了细胞活力、凋亡和增殖,在体外检测了细胞存活和凋亡。通过使用质谱仪进行靶向脂质组学研究,量化细胞内的鞘磷脂水平,从而证实了 UGCG 的抑制功效。对鞘脂生物合成途径的其他抑制剂也进行了类似的评估。阻断UGCG可明显降低细胞活力和增殖,突出了UGCG在CLL中的致癌作用。细胞内 GluCer 水平的显著降低证实了 UGCG 的有效抑制作用。UGCG 抑制剂与伊布替尼的联合用药具有协同作用。针对鞘磷脂代谢替代途径的抑制剂,如鞘磷脂激酶抑制剂SKI-II,无论是单独使用还是与伊布替尼联合使用,也都表现出了良好的治疗效果,从而加强了鞘磷脂在CLL细胞中的致癌影响。靶向鞘脂代谢,尤其是 UGCG 通路,是一种很有前景的治疗策略,也是一种潜在治疗 CLL 患者的联合疗法,值得进一步研究。
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来源期刊
Clinical and Experimental Medicine
Clinical and Experimental Medicine 医学-医学:研究与实验
CiteScore
4.80
自引率
2.20%
发文量
159
审稿时长
2.5 months
期刊介绍: Clinical and Experimental Medicine (CEM) is a multidisciplinary journal that aims to be a forum of scientific excellence and information exchange in relation to the basic and clinical features of the following fields: hematology, onco-hematology, oncology, virology, immunology, and rheumatology. The journal publishes reviews and editorials, experimental and preclinical studies, translational research, prospectively designed clinical trials, and epidemiological studies. Papers containing new clinical or experimental data that are likely to contribute to changes in clinical practice or the way in which a disease is thought about will be given priority due to their immediate importance. Case reports will be accepted on an exceptional basis only, and their submission is discouraged. The major criteria for publication are clarity, scientific soundness, and advances in knowledge. In compliance with the overwhelmingly prevailing request by the international scientific community, and with respect for eco-compatibility issues, CEM is now published exclusively online.
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