RETRACTED ARTICLE: Aberrant mannosylation profile and FTX/miR-342/ALG3-axiscontribute to development of drug resistance in acute myeloid leukemia

Bing Liu,Yang Xiao,Xiaolu Ma,Qianqian Liu,Shimeng Pan,Li Jia

doi:10.1038/s41419-018-0706-7

Abstract

Drug-resistance is a major problem in acute myeloid leukemia (AML)chemotherapy. Aberrant changes in specific N-glycans have been observed in leukemia multidrug resistance (MDR).MicroRNAs (miRNAs) and long non coding RNAs (lncRNAs) act as key players in thedevelopment of AML resistance to chemotherapy. In the present study, the N-glycan profiles of membrane proteins were analyzedfrom adriamycin (ADR)-resistant U937/ADR cells and sensitive line U937 cells usingmass spectrometry (MS). The composition profiling of high-mannose N-glycans differed in U937/ADR and U937 cell lines.Lectin microarray showed that the strong binding of membrane proteins was observedfor MAN-M and ConA lectins, which were specific for mannose. These binding were alsovalidated by flow cytometry. Importantly, the alteration of high-mannose N-glycan was further confirmed by detecting the enzymelevel of ALG family. The altered level of ALG3 was found corresponding to thedrug-resistant phenotype of AML cell lines both in vitro and in vivo.Mechanistically, miR-342 was found to be dysregulated and inversely correlated toALG3 expression, targeting its 3′-UTR. LncRNA FTX was a direct target of miR-342 andpositively modulated ALG3 expression by competitively binding miR-342 in AML celllines. Functionally, we found that FTX directly interacted with miR-342 to regulateALG3 expression and function, including ADR-resistant cell growth and apoptosis. Theobservation suggested that high-mannose N-glycansand mannosyltransferase ALG3 affected drug-resistance in AML cells. FTX/miR-342/ALG3axis could potentially be used for the targets to overcome therapeutic resistance inAML.

Highlights

MiR-342/ALG3-axis contribute to dmeyveeloloidpmleeunktemofiadrug resistance in acute LE Bing Liu[1], Xiaolu Ma1,2, Qianqian Liu[1], Yang Xiao[1], Shimeng Pan[1] and Li Jia 1 IC Abstract
Analysis of Nglycans by MALDI-TOF mass spectrometry (MS) represents a new paradigm in cancer biomarker studies
The N-linked glycans were monitored during the drug-resistance of acute myeloid leukemia (AML) cells

Summary

Materials and methods

Clinical samples and cell culture microarrays were blocked for 3 h in 50 μM ethethanola-. Quantitative real-time PCR Total RNA was isolated from PBMC samples and AML cell lines by Trizol reagent (Invitrogen, USA). T Apoptosis rate of cells was analyzed by FACS Calibur flow cytometer (Becton-Dickinson, CA, USA), detecting the. The cells were seeded into 6-well plates and transfection was performed using Lipofectamine 3000 (Invitrogen). The transfected cells were collected for luciferase detection by the dual-luciferase reporter gene assay system (Promega, Madison, WI, USA). RNA immunoprecipitation (RIP) assay The Magna RIPTM RNA Binding Protein Immunoprecipitation Kit (Millipore, Bedford, MA, USA) was utilized to perform RIP assay. Fluores- conjugated with human anti-Ago[2] antibody (Millipore) or cence intensity was measured by Cell Quest software. Drug susceptibility was measured using cell counting RNA, which better illustrated the potential the binding kit-8 (CCK-8; KeyGEN, Nanjing, China). L used for multiple groups. *P < 0.05 was considered to be statistically significant

C Results I N-Glycan profles of AML cell lines

C No statistically significant differences were found in other

Findings

Discussion