TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1

Fei Lu,Tao Sun,Yan Wang,Xinlu Wang,Jingjing Ye,Daoxin Ma,Yihua Pang,Ruiqing Wang,Chunyan Ji,Peng Li,Min Ji,Yanan Zhao,Jingxin Li,Na Liu

doi:10.1186/s13046-020-01658-z

Abstract

BackgroundChemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance.MethodsThe expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models.ResultsUpregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival.ConclusionOur data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target.

Highlights

Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms
We showed that tumor necrosis factor ɑ-induced protein 8 (TNFAIP8) suppresses apoptosis and promotes chemoresistance in AML by interacting with Rac family small GTPase 1 (Rac1) to activate the extracellular signal-regulated kinase (ERK) pathway
Both in vitro and in vivo, our study strongly indicates that targeting TNFAIP8 is a promising strategy for overcoming AML chemoresistance

Summary

Introduction

Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. We aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance. An expanding body of evidence has illustrated that dysregulated expression of anti-apoptotic molecules, such as BCL2 and MCL-1, renders malignant cells resistant to the proapoptotic effects of cytotoxic agents [6,7,8]. Inhibition of these molecules has increased chemosensitivity in AML, underlining the crucial role of apoptosis dysregulation in AML chemoresistance [9,10,11]. There arise demands for further exploration of new candidates in apoptosis regulation network in AML

Objectives

Methods

Results

Discussion

Conclusion