Bioactive Lipids as Chronic Myeloid Leukemia’s Potential Biomarkers for Disease Progression and Response to Tyrosine Kinase Inhibitors

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that expresses the Philadelphia chromosome and constitutively activated Bcr-Abl tyrosine kinase in hematopoietic progenitor cells. Bcr-Abl tyrosine-kinase inhibitors (TKI) do not definitively cure all CML patients. The efficacy of TKI is reduced in CML patients in the blastic phase—the most severe phase of the disease—and resistance to this drug has emerged. There is limited knowledge on the underlying mechanisms of disease progression and resistance to TKI beyond BCR-ABL1, as well as on the impact of TKI treatment and disease progression on the metabolome of CML patients. The present study reports the metabolomic profiles of CML patients at different phases of the disease treated with TKI. The plasma metabolites from CML patients were analyzed using liquid chromatography, mass spectrometry, and bioinformatics. Distinct metabolic patterns were identified for CML patients at different phases of the disease and for those who were resistant to TKI. The lipid metabolism in CML patients at advanced phases and TKI-resistant patients is reprogrammed, as detected by analysis of metabolomic data. CML patients who were responsive and resistant to TKI therapy exhibited distinct enriched pathways. In addition, ceramide levels were higher and sphingomyelin levels were lower in resistant patients compared with control and CML groups. Taken together, the results here reported established metabolic profiles of CML patients who progressed to advanced phases of the disease and failed to respond to TKI therapy as well as patients in remission. In the future, an expanded study on CML metabolomics may provide new potential prognostic markers for disease progression and response to therapy.

Metabolic profile analysis in hematological malignancies

“…The serum metabolic profile of patients responding and refractory to treatment with tyrosine kinase inhibitors has been assessed and compared. Lipid metabolism has been shown to differ significantly between these groups [26]. Notably higher ceramide and lower sphingomyelin levels were found in the serum of TKI-resistant patients compared to the treatment-resistant group.…”

“…These scales, in addition to remaining reliable, validated tools for predicting patient outcomes, might also be helpful in individualized, risk-adapted initial treatment decisions and predicting outcomes for appropriate of treatment response. The final section describes the challenges underlying metabolomics-based experiments and discusses the potential pitfalls of the analytical process, including study design and sample collection (Table I [18,19,[21][22][23][24][25][26][27][28]).…”

“…cont.). Summary of selected metabolomic studies (compiled from[18,19,[21][22][23][24][25][26][27][28])Acta Haematologica Polonica 2024, vol. 55, no.…”

Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies

“…Thus, the elevation of ceramide induced apoptosis and rescued sensitivity to TKIs [ 254 ]. The sphingolipidomics profile was also recently analyzed in plasma from patients at different stages of CML, including TKI-resistant patients, and it was found that ceramide levels were increased in TKI-resistant patients while SM and S1P levels were decreased in the chronic- and accelerated-phase CML [ 255 ]. These results seem to be discordant from sphingolipid levels measured in primary cells, particularly in the case of TKI resistance and this might be due to measurements in plasma versus cells [ 254 ].…”