Modification Of Sialylation Mediates Multidrug Resistance In Human Acute Myeloid Leukemia

Objective: To investigate the differential expression of20sialyltransferase (ST)genes in the both acute myeloid leukemia (AML) cell lines and bone marrowmononuclear cells (BMMC) of AML patients, and to clarify the correlation of ST genesand multidrug resistance of AML. To further predict and diagnose AML multidrugresistance (MDR), and provide a new therapeutic strategy and target point of AML.Methods:(1) Using mass spectrometry for glycan composition, we compared the N-glycancomposition of drug-resistant HL60/ADR cells with parental HL60cells.(2) Using real-time PCR for quantification of ST genes, we compared thedifferential expression (i.e.,>3-fold higher) of ST genes in the3pairs of AML cell linesand bone marrow mononuclear cells (BMMC) of AML patients.(3) Manipulating the differentially expressed ST genes, to detect thechemosensitivity to anti-tumor drugs in vitro and in vivo. The effect of alteredexpression of ST genes on the activity of PI3K/Akt signaling pathway and theproportionally mutative expression of P-gp and MRP1was also observed.(4) Blocking the PI3K/Akt pathway by its specific inhibitor LY294002or AktsiRNA, the chemosensitivity of HL60/ADR cells was analyzed.Results:(1) The N-glycan compositions were different in HL60/ADR cells, as comparedwith those in HL60cells.(2)7ST genes (i.e.,>3-fold higher) were differentially expressed in3pairs ofAML cell lines and BMMC of AML patients.(3) The silencing of glycogene ST8SIA4and overexpression of glycogeneST3GAL5in HL60/ADR cells resulted in increased chemosensitivity to anti-tumordrugs and decreased expression of the main molecules of PI3K/Akt signaling pathway, P-gp and MRP1(P<0.05), opposite results were obtained in HL60-ST3GAL5shRNAcells and HL60/ST8SIA4cells.(4) Blocking the PI3K/Akt pathway by its specific inhibitor LY294002or AktsiRNA resulted in the decreased expression of the main molecules of PI3K/Aktsignaling pathway, and chemoresistance of HL60/ADR cells.Conclusion:(1) The expression of ST genes was different in3pairs of AML cell lines andBMMC of AML patients. These characteristic alterations are associated with multidrugresistance in AML.(2) Sialylation involved in the development of MDR of AML cells probablythrough ST3GAL5or ST8SIA4regulating the activity of PI3K/Akt signaling and theexpression of P-gp and MRP1.