G3BP2-Mediated Venetoclax Resistance via ELF1-Driven MCL1 Transcription in Acute Myeloid Leukemia: Mechanisms and Therapeutic Implications

Highlights

• G3BP2 upregulation in AML is linked to venetoclax resistance and poor clinical outcomes.
• G3BP2 enhances AML cell survival by stabilizing ELF1 mRNA, which transcriptionally activates anti-apoptotic MCL1.
• Pharmacologic inhibition of G3BP2 by C108 synergizes with venetoclax to overcome resistance, improving survival in AML preclinical models.
• The G3BP2-ELF1-MCL1 axis represents a promising target for next-generation therapeutic strategies against AML.

Background

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by clonal proliferation of myeloid blast cells with impaired differentiation. Despite advances in chemotherapy and targeted agents, the prognosis remains poor for many patients, especially those with relapsed/refractory disease. Venetoclax, a selective BCL2 inhibitor, has emerged as a major therapeutic advancement in AML, demonstrating efficacy particularly in elderly or unfit patients, often in combination with hypomethylating agents or low-dose cytarabine.

However, acquired resistance to venetoclax limits its long-term clinical benefits. Mechanistically, upregulation of anti-apoptotic proteins such as MCL1 is a frequent cause of venetoclax resistance, as MCL1 can substitute for BCL2 inhibition to maintain leukemia cell survival. Understanding regulatory pathways that augment MCL1 expression in AML is critical for devising strategies to overcome therapeutic resistance.

G3BP2, an RNA-binding protein and stress granule component, is known to be overexpressed in various solid tumors, where it promotes survival and chemoresistance. Yet, its function in myeloid leukemia and contribution to BCL2 inhibitor resistance remained unexplored until recently.

Key Content

Biological Role of G3BP2 in AML and Venetoclax Resistance

Recent integrated analyses have highlighted that increased G3BP2 expression correlates with poor overall survival and venetoclax resistance across AML patient cohorts. Functional studies demonstrate that genetic depletion of G3BP2 in AML cell lines and murine xenograft models results in reduced proliferation and increased apoptosis, indicating its role as a pro-survival factor.

Mechanistic Insights: G3BP2, ELF1, and MCL1 Regulation

Intriguingly, the anti-apoptotic protein MCL1, a key driver of venetoclax resistance, is co-expressed with G3BP2. Functional assays reveal that G3BP2 does not bind directly to MCL1 mRNA or protein; instead, G3BP2 binds and stabilizes the mRNA of ELF1, a transcription factor. ELF1, upon stabilization, binds to specific sequences in the MCL1 promoter region to enhance its transcription.

Inhibition of G3BP2 leads to decreased ELF1 mRNA stability, downregulation of ELF1 protein levels, and consequent reduction in MCL1 transcription. Thus, G3BP2 indirectly sustains MCL1 expression through post-transcriptional regulation of ELF1 mRNA, establishing a novel regulatory axis contributing to venetoclax resistance.

Therapeutic Targeting: Synergistic Activity of C108 and Venetoclax

A small molecule inhibitor of G3BP2, termed C108, has demonstrated pronounced antileukemic effects both in vitro and in patient-derived xenograft (PDX) models when combined with venetoclax. C108-mediated G3BP2 inhibition destabilizes ELF1 mRNA, lowers MCL1 expression, and sensitizes AML cells to venetoclax-induced apoptosis.

This combination significantly extends overall survival in AML murine models, offering a compelling preclinical rationale for combination therapy trials. C108 alone exhibits limited toxicity, and its use with venetoclax appears promising, particularly in AML subsets exhibiting high G3BP2 and MCL1 expression profiles.

Complementary Evidence and Related Pathways

Prior studies established the critical role of MCL1 upregulation in venetoclax resistance, with efforts underway to develop MCL1 inhibitors. However, direct MCL1 inhibitors face challenges related to toxicity and therapeutic window. Targeting upstream regulators such as G3BP2-ELF1 offers a novel indirect therapeutic angle with potentially greater specificity and reduced adverse effects.

Moreover, RNA-binding proteins have increasingly been recognized as key modulators of leukemogenesis and drug resistance, making G3BP2 an attractive target in the broader context of post-transcriptional regulation in AML.

Expert Commentary

The identification of G3BP2 as a mediator of venetoclax resistance via stabilization of ELF1 mRNA enriches our understanding of resistance mechanisms in AML. This study provides compelling evidence for a previously unrecognized RNA-binding protein-centric axis controlling anti-apoptotic gene expression.

From a clinical perspective, this underscores the importance of molecular profiling including G3BP2 and ELF1 expression to identify patients likely to benefit from combination therapies targeting this pathway. Furthermore, G3BP2 inhibitors such as C108 could serve as promising adjuncts to current venetoclax regimens, potentially overcoming resistance with manageable toxicity.

Nevertheless, translation to human trials will require careful evaluation of pharmacodynamics, off-target effects, and resistance mechanisms to G3BP2 inhibition itself. It is also imperative to investigate whether other transcription factors or mRNA transcripts are similarly stabilized by G3BP2, which could influence broader cellular processes.

Current AML treatment guidelines (e.g., NCCN, ELN) have yet to incorporate RNA-binding protein targets, presenting an emerging area of translational research. Incorporation of G3BP2 and ELF1 status into prognostic models may enhance risk stratification and guide personalized therapeutic decision-making.

Conclusion

The elucidation of the G3BP2-ELF1-MCL1 regulatory axis marks a significant advance in understanding mechanisms of venetoclax resistance in AML. By stabilizing ELF1 mRNA, G3BP2 indirectly upregulates MCL1, promoting leukemia cell survival despite BCL2 inhibition.

Pharmacological targeting of G3BP2 with C108 combined with venetoclax shows synergistic antileukemic activity, prolonging survival in preclinical models and paving the way for clinical development. This approach offers a novel and promising strategy to enhance venetoclax efficacy, particularly for patients with high G3BP2 expression and refractory disease.

Future studies should focus on validating these findings in clinical trials, exploring biomarker-guided therapy, and further delineating the broader role of RNA-binding proteins in AML pathobiology and drug resistance.

References

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