Xie Yinyin, Zeng Qinghua, Chen Zhiwei, Song Jiachun, Wang Fuhui, Liu Dan, Sun Xiaojian, Zhang Yuanliang, Huang Qiuhua
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, China.
Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Cell Death Dis. 2025 Apr 13;16(1):282. doi: 10.1038/s41419-025-07594-0.
Chronic myeloid leukemia (CML) is primarily driven by the BCR::ABL1 oncoprotein, which has potent tyrosine kinase activity. BCR::ABL1 has been shown to facilitate several metabolic processes, including glycolysis, lipid synthesis, and protein synthesis in vitro. However, the altered metabolic profile in vivo remains poorly understood. Using Scl/tTA-BCR::ABL1 mice as a model, we conducted an analysis of plasma metabolites at different stages following BCR::ABL1 induction. Metabolites involved in sphingolipid and thiamine metabolism were significantly altered at the early stage of CML, while the tricarboxylic acid (TCA) cycle metabolites were altered during disease progression. Among these metabolic changes, sphingolipid metabolism is of particular significance. Inhibition of sphingolipid metabolism had a more pronounced effect on the growth and survival fate of K562 cells compared to thiamine metabolism inhibition. Furthermore, knockdown of sphingosine kinase 1 (SPHK1) resulted in extensive metabolic remodeling, affecting lipid, energy, and heme metabolism. Pharmacological targeting of sphingolipid metabolism appeared to attenuate the development of CML. Our study also demonstrated that BCR::ABL1 triggers ERK-dependent phosphorylation of SphK1, leading to aberrant activation of sphingolipid metabolism, which in turn has a positive feedback effect on BCR/ABL expression. These findings highlight the dominant role of sphingolipid metabolism in BCR::ABL1-induced metabolic reprogramming in CML.
慢性髓性白血病（CML）主要由具有强大酪氨酸激酶活性的BCR::ABL1癌蛋白驱动。体外研究表明，BCR::ABL1可促进多种代谢过程，包括糖酵解、脂质合成和蛋白质合成。然而，体内代谢谱的改变仍知之甚少。我们以Scl/tTA-BCR::ABL1小鼠为模型，对BCR::ABL1诱导后不同阶段的血浆代谢物进行了分析。在CML早期，参与鞘脂和硫胺素代谢的代谢物发生了显著变化，而在疾病进展过程中，三羧酸（TCA）循环代谢物发生了改变。在这些代谢变化中，鞘脂代谢尤为重要。与抑制硫胺素代谢相比，抑制鞘脂代谢对K562细胞的生长和存活命运有更显著的影响。此外，敲低鞘氨醇激酶1（SPHK1）导致广泛的代谢重塑，影响脂质、能量和血红素代谢。靶向鞘脂代谢的药物似乎可减缓CML的发展。我们的研究还表明，BCR::ABL1触发ERK依赖的SphK1磷酸化，导致鞘脂代谢异常激活，进而对BCR/ABL表达产生正反馈作用。这些发现突出了鞘脂代谢在BCR::ABL1诱导的CML代谢重编程中的主导作用。
