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.

Keywords: bioactive lipids; chronic myeloid leukemia; pathogenesis and metabolomics; tyrosine kinasa inhibitor; tyrosine kinase inhibitors.

Figure 1

Metabolites differentially abundant in CML patients in comparison with the control group. (A–C) Volcano plots to compare down- and upregulated metabolites in (A). CML patients in the chronic phase (CP; n = 10) and control group (CT; n = 9); (B) CML patients in the advanced phase (AP, n = 13) and control group (CT); (C) CML patients in remission post-TKI therapy (RM; n = 6) and control group (CT). (D) Venn diagram of differentially abundant metabolites in each group, after comparison. (E, F) Scatter-plots of the amount of top predicted metabolites in CML patients and the control group. Sphingosine-1-phosphate was less abundant in CML-AP patients than in the control group. N-Acetylneuraminic acid was more abundant in patients in remission than in control subjects and CML-CP and CML-AP patients. (G) The most representative metabolic pathways in CML patients, compared with the control group. The circle size represents the number of differentially abundant metabolites, and the circle color means the degree of significance (p-value magnitude) after comparison among groups. Significant metabolite features were identified by ANOVA with repeated measures, associated with Tukey’s multiple comparisons test (^* p < 0.05; ^** p < 0.01).

Figure 2

Sphingolipid profile in chronic myeloid leukemia patients. Relative frequency of sphingolipid classes in the control group and patients in the chronic (CP) and advanced (AP) phases of the disease and in remission post-TKI therapy (RM). SMSs, Sphingomyelin synthase; SMases, Sphingomyelinase; CK, ceramide kinase; C1PP, ceramide-1-phosphate phosphatase; GCS, glucosylceramide synthase; GCases, Glucocerebrosidase; CS, ceramide synthases; CDases, ceramidases; GalCS, galactosylceramide synthase; Gal-CDase, galactosylceramidase; SK, sphingosine kinase; S1PP, spingosine-1-phosphate phosphatase.

Figure 3

Dynamic of the abundance of metabolite features associated with disease progression and response to TKI therapy. (A) One-way hierarchical clustering based on the intensity of highly significant metabolite features selected by ANOVA. (B) Metabolic pathways enriched by significant metabolite features. (C) Up- and downregulated abundant metabolites in patients in advanced (AP)/resistant (RT) vs. chronic phase (CP), AP/RT vs. remission post-TKI (RM), and CP vs. RM. (D) Metabolic pathways enriched by significant metabolite features. The circle size represents the number of differentially abundant metabolites, and the circle color means the degree of significance (p-value magnitude) after comparison between the control and CML patient groups.