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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-<jats:italic>BCR::ABL1<\/jats:italic> mice as a model, we conducted an analysis of plasma metabolites at different stages following <jats:italic>BCR::ABL1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41419-025-07594-0","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T23:24:26Z","timestamp":1744500266000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dysregulation of sphingolipid metabolism contributes to the pathogenesis of chronic myeloid leukemia"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8882-3939","authenticated-orcid":false,"given":"Yinyin","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuhui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8826-4614","authenticated-orcid":false,"given":"Xiaojian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanliang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5701-0117","authenticated-orcid":false,"given":"Qiuhua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,13]]},"reference":[{"key":"7594_CR1","doi-asserted-by":"publisher","first-page":"eaaw5473","DOI":"10.1126\/science.aaw5473","volume":"368","author":"B Faubert","year":"2020","unstructured":"Faubert B, Solmonson A, DeBerardinis RJ. 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