MiR-652-5p elevated glycolysis level by targeting TIGAR in T-cell acute lymphoblastic leukemia

Shan Liu,Lamei Zeng,Hongyu Su,Shi Tang,Haiyan Liu,Haobiao Wang,Lin Zou,Wei Guo,Yi Shu,Xiaoyan Zhou,Ziyang Liu,Li Yang

doi:10.1038/s41419-022-04600-7

Abstract

The effect of glycolysis remains largely elusive in acute T lymphoblastic leukemia (T-ALL). Increasing evidence has indicated that the dysregulation of miRNAs is involved in glycolysis, by targeting the genes coding glycolysis rate-limiting enzymes. In our previous studies, we found that overexpression of the ARRB1-derived miR-223 sponge repressed T-ALL progress and reduced the expression of miR-652-5p. However, little is known about miR-652-5p on T-ALL. Here, we showed that impaired miR-652-5p expression inhibited growth, promoted apoptosis of T-ALL cells in vitro and prolonged overall survival (OS) in vivo. Based on the GO enrichment of miR-652-5p target genes, we uncovered that impaired miR-652-5p decreased glycolysis, including reduced the lactate, pyruvate, ATP level and the total extracellular acidification rate (ECAR), elevated oxygen consumption rate (OCR) in T-ALL cell lines. Mechanically, miR-652-5p targeted the 3ʹUTR of Tigar mRNA and inhibited its expression. Furthermore, the alteration of glycosis level was attributed to Tigar overexpression, consistent with the effect of impaired miR-652-5p. Additionally, Tigar suppressed the expression of PFKFB3, a glycolysis rate-limiting enzyme, in vivo and in vitro. Taken together, our results demonstrate that impaired miR-652-5p/Tigar axis could repress glycolysis, thus to slow growth of T-ALL cells, which support miR-652-5p as a novel potential drug target for T-ALL therapeutics.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) was recognized as an independent disease in the 1970s, after discovering thymusassociated markers expressed on the surface of leukemic cells from pediatric patients [1]
Given that miRs are reported to affect glycolysis level by targeting the genes coding glycolysis rate-limiting enzymes, such as PFKFB3 [16], GLUT-1 [17], and PFK1 [18], we reported that impaired miR-652-5p could slow the cell growth of T-ALL in vitro and prolong the survival time in vivo
The expression of miR-652-5p was diverse in T-ALL cell lines; increased expression was observed in Jurkat and Molt-4 cells (Supplementary Fig. 1D)

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) was recognized as an independent disease in the 1970s, after discovering thymusassociated markers expressed on the surface of leukemic cells from pediatric patients [1]. The overall cure rates have increased to 80% in recent years due to improved diagnostic technologies and new treatment regimens [2]. The 5-year event-free survival rate of T-ALL is still significantly lower than that of other acute lymphoblastic leukemias [3]. The development of leukemia relies on high levels of glycolysis which may be a target for therapeutic intervention in acute myeloid leukemia [5, 6]. The increased glycolysis level is found in T-ALL [7,8,9], and is elevated by oncogenes such as NOTCH [7] and RUNX2 [9]

Methods

Results

Conclusion