TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1
The tumor necrosis factor induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, has been implicated in chemoresistance of several types of neoplasms, but its role in AML remains to be elucidated. In this study, upregulated TNFAIP8 expression was found in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was identified to contribute to its aberrant expression. Forced expression of TNFAIP8 protected cells from apoptosis induced by chemotherapeutic agents and increased drug resistance. Importantly, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the extracellular signal-regulated kinase (ERK) signaling pathway through an interaction with Rac family small GTPase 1 (Rac1). In vivo experiments showed that TNFAIP8 suppression lowered leukemia infiltration and improved survival. Taken together, our 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. Overall design: Gene expression analysis by RNA-seq of K562/A02 cells with or without lentivirus-mediated knockdown of TNFAIP8