PGK1, a promising biomarker and therapeutic target for patients with acute myeloid leukemia who are susceptible to disease relapse

Background: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out the glycolytic enzyme, phosphoglycerate kinase 1 (PGK1) whether participate in the progression of acute myeloid leukemia (AML) and its possible mechanisms. Methods: Four datasets (GSE106096, GSE75086, GSE107968 and GSE106748) containing 30 leukemic blast cell samples of AML at diagnosis, 17 leukemic blast cell samples of AML relapse and 3 bone marrow CD34+ cell samples of healthy donors were downloaded from Gene Expression Omnibus (GEO) database and PGK1 was screened out as a potential survival biomarker in AML. Then we did a series of clinical sample verifications and gene set enrichment analysis (GSEA) focusing on PGK1. We further knocked down expression of PGK1 in myelogenous leukemia cell lines and explored its potential effects. Results: PGK1 expression was up-regulated among AML at diagnosis versus healthy control, AML relapse versus AML at diagnosis and AML relapse versus healthy control datasets. Through a serial of bioinformatic analyses (differentially expressed genes [DEGs] selection, function and pathway enrichments and protein-protein interaction [PPI] network establishment), PGK1 was identified as the most meaningful gene in AML progression. Furthermore, the generally high expression of PGK1 was confirmed in AML samples comparing with healthy controls in our single center and the high-expression PGK1 was associated with a comparatively low complete remission (CR) rate, a significantly high 5-year cumulative incidence of relapse (CIR), a poor 5-year event-free survival (EFS) rate, and a poor 5-year overall survival (OS) rate. The GSEA revealed that high-expression PGK1 in AML was associated with many pathways including cytosolic DNA sensing, pentose phosphate, base excision repair and DNA replication. In vitro, the transfected U937 and K562 cells with PGK1 knock-down showed decreased cell viability and increased apoptotic rate. PGK1 inhibition could greatly decrease the half maximal inhibitory concentrations (IC50) of cytarabine (Ara-C) and daunorubicin (DNR) in U937 and K562 cell lines.Conclusions: High-expression PGK1 was associated with poor prognosis in AML. PGK1 may serve to predict the AML progression and provide a novel therapeutic target for AML.