The Biological Effects Of Epoxyeicosatrienoic Acids In Chronic Myeloid Leukemia Stem Progenitor Cells

Background: In the new era of the molecular targeted therapy of tyrosine kinase inhibitors(TKIs),chronic myeloid leukemia has been a sort of chronic disease.Nonetheless,approximately half of the chronic myeloid leukemia(CML)patients in long-term complete molecular remission could relapse after withdrawal of tyrosine kinase inhibitors.At the same time,the chronic myeloid leukemia stem cells(LSCs)could be also detected in partial chronic myeloid leukemia patients with complete molecular response.All of these may to some extent indicate that the tyrosine kinase inhibitors could not eliminate the dormant leukemia stem cells.Owing to the critical role of lipid metabolism in the maintenance of leukemia stem cells,Epoxyeicosatrienoic acids(EETs),one important bioactive lipid mediator of lipid metabolism,are closely related to all kinds of tumors.As a result,our research would further deeply study the biological effects of EETs in the chronic myeloid leukemia stem progenitor cells in order to find the novel therapeutic target to erase LSCs.Methods: In our study,the level of 14,15-EET in bone marrow serum of CML patients was detected by ELISA.The mRNA expression of CYP2J2,CYP28 and CYP2C9 was determined by fluorescent quantitative RT-PCR.The biological effects of EETs and 17-ODYA in LSCs were analyzed by cell proliferation,apoptosis and differentiatial clone formation assays.Results: The median 14,15-EET level was significantly higher in CML patients than healthy controls.But there was no significant difference between different phases of CML,before and after treatment of TKIs or even diverse molecular responses.Moreover,the mRNA level of CYP2J2,CYP28 and CYP2C9 was not consistent with the level of 14,15-EET.While 14,15-EET had no effect on proliferation and apoptosis of CML CD34+ cells,17-ODYA could reduce cell proliferation and promote cell apoptosis.Furthermore,14,15-EET could rescue these effects of 17-ODYA treatment.In addition,14,15-EET could promote differentiatial clone formation of CML CD34+ cells.Conversely,17-ODYA had the opposite role.Conclusions: The present study shows that elevated 14,15-EET levels in bone marrow microenvironment of CML patients are probably associated with the differentiation of chronic myeloid leukemia stem progenitor cells.