Aberrant Mannosylation Profile and FTX/miR-342/ALG3-axis Contribute to Development of Drug Resistance in Acute Myeloid Leukemia

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2018 Jun 9

PMID 29880818

Citations 24

Authors

Bing Liu

Xiaolu Ma

Qianqian Liu

Yang Xiao

Shimeng Pan

Li Jia

Affiliations

Soon will be listed here.

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 the development of AML resistance to chemotherapy. In the present study, the N-glycan profiles of membrane proteins were analyzed from adriamycin (ADR)-resistant U937/ADR cells and sensitive line U937 cells using mass 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 observed for MAN-M and ConA lectins, which were specific for mannose. These binding were also validated by flow cytometry. Importantly, the alteration of high-mannose N-glycan was further confirmed by detecting the enzyme level of ALG family. The altered level of ALG3 was found corresponding to the drug-resistant phenotype of AML cell lines both in vitro and in vivo. Mechanistically, miR-342 was found to be dysregulated and inversely correlated to ALG3 expression, targeting its 3'-UTR. LncRNA FTX was a direct target of miR-342 and positively modulated ALG3 expression by competitively binding miR-342 in AML cell lines. Functionally, we found that FTX directly interacted with miR-342 to regulate ALG3 expression and function, including ADR-resistant cell growth and apoptosis. The observation suggested that high-mannose N-glycans and mannosyltransferase ALG3 affected drug-resistance in AML cells. FTX/miR-342/ALG3 axis could potentially be used for the targets to overcome therapeutic resistance in AML.

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