Eicosanoids as hallmarks of chronic myeloid leukemia progression and resistance to tki

Chronic myeloid leukemia (CML) is a Ph-positive myeloproliferative neoplasm giving rise to BCR-ABL1 oncogene. Usually, the disease is diagnosed in the chronic phase (CML-CP) with uncontrolled clonal expansion and high white blood cell count. Without therapy intervention, CML progress to advanced phases (accelerated and blastic phases; CML-AP). The Tyrosine Kinase Inhibitors (TKI) are the first-line therapeutic approach for CML. TKI targets the BCR-ABL tyrosine kinase activity and restrain the disease. The knowledge about the mechanisms involved in disease progression and resistance to TKI, beyond BCR-ABL1, is limited. The relation among TKI treatment, disease progression and eicosanoids pattern in CML is unknown. Lipid mediators were quantified in healthy individuals (Controls; n = 9) as well as in CML patients in CP (n = 10), CML-AP (n = 13) and CML patients in molecular remission post-TKI therapy (RM; n = 6) using Liquid Chromatography/Mass Spectrometry (LC/MS). Mass spectral data were acquired with negative electrospray ionization. ProteinWizard was used to convert files to be used in bioinformatic subsequent analysis. Mummichog software was used for metabolic pathway enrichment analysis. Heatmaps were generated with the R package gplots and hierarchical clustering was performed with the R package amap with Spearman distance method and ward linkage algorithm. Volcano and bubble plots were obtained with the package ggplot2. We described the metabolomic profiles of CML in different phases and post-TKI therapy. The metabolic patterns were able to distinguish the CML patients in different phases and resistant to TKI. The metabolomic results suggested an association between reprogramming in lipid metabolism and CML progression and resistance to TKI therapy. CML patients showed to be a lower producer of some eicosanoids compared to controls. Interestingly, AP-CML produced less 12-HETE and EPA than CP-CML patients. CML patients in molecular remission produced more EPA in comparison with each other group. Taken together, the results established the eicosanoid profile of CML patients who progress to advanced phases and fail to respond to TKI.