What question did this study set out to answer?

This study aims to investigate the role of G3BP2 in venetoclax resistance in acute myeloid leukemia and its regulation of MCL1 transcription.

July 22, 2026Open Access

G3BP2 confers venetoclax resistance by stabilizing ELF1-mediated MCL1 transcription in acute myeloid leukemia

ZCZ ChenCentral South University of Forestry and Technology YCYuanhua CaiFujian Medical University YWYuxing WangSouth China Agricultural University

Key Points

This study aims to investigate the role of G3BP2 in venetoclax resistance in acute myeloid leukemia and its regulation of MCL1 transcription.
Conducted integrated analysis of G3BP2 expression levels in AML cohorts.
Examined the effects of G3BP2 deficiency on AML cell proliferation and apoptosis in xenograft models.
Validated the interaction between G3BP2 and ELF1 mRNA affecting MCL1 transcriptional activity.
G3BP2 deficiency significantly inhibited AML cell proliferation and increased apoptosis.
High G3BP2 expression correlated with elevated MCL1 levels and poor patient outcomes.
Combination treatment of C108 and venetoclax significantly enhanced therapeutic efficacy and prolonged overall survival in AML model mice.

Abstract

Venetoclax is a promising treatment for acute myeloid leukemia (AML) patients, but resistance occurs following the upregulation of MCL1. The RNA-binding protein G3BP2 is upregulated in various solid tumors, and targeting G3BP2 has been shown to restore chemosensitivity. However, the role of G3BP2 in AML development and venetoclax resistance remains unknown. Herein, an integrated analysis revealed that G3BP2 confers venetoclax resistance and correlates with poor outcomes in AML. G3BP2 deficiency inhibits AML proliferation and induces apoptosis in AML cells and xenograft mice. G3BP2 expression aligns with MCL1 levels across AML cohorts, and the regulatory effect of G3BP2 on MCL1 was validated in AML cells. Notably, G3BP2 and MCL1 do not interact directly; instead, G3BP2 interacts with ELF1 mRNA to increase its stability. The transcription factor ELF1 binds to the MCL1 promoter to induce its expression, which can be attenuated by G3BP2 inhibition. Furthermore, C108-mediated inhibition of G3BP2, in combination with venetoclax, has anticancer effects in primary AML cells and in patient-derived xenografts (PDX). C108 increases the therapeutic efficacy of venetoclax and their combination prolongs overall survival (OS) in AML model mice. These findings identify G3BP2 as a regulator of venetoclax resistance through ELF1-mediated MCL1 transcription, suggesting new therapeutic strategies.

Ask AI

Helpful

Bookmark

View Full Paper