Cytoplasmic localization of qki mediates therapeutic resistance and immune evasion

Abstract

Abstract The combination of the BCL2 inhibitor venetoclax with the hypomethylating agent 5-azacytidine has revolutionized AML treatment in older patients. However, resistance to venetoclax combination therapy remains a major clinical challenge, with around 30% of patients failing to respond or relapsing. Here, we employed and RNA-binding protein focused CRISPR activation screen and identified the m7G reader protein Quaking (QKI) as a key post-transcriptional driver of venetoclax resistance. Genetic deletion of QKI sensitized AML cells to venetoclax and its combination with 5-azacytidine. Moreover, we demonstrated that overexpression of three isoforms (QKI-6, QKI-7, and QKI-7b) promoted venetoclax resistance through their subcellular cytoplasmic localization. Mechanistically, we showed that ZFP36L1, which drives monocytic AML differentiation and venetoclax resistance in AML patients,is a direct target of cytoplasmic QKI and the m7G writer METTL1. Furthermore, transcriptomic profiling revealed that QKI regulates the immune checkpoint inhibitor CD276, which we found is upregulated in AML patient samples. Finally, we assessed the combination of venetoclax with enoblituzumab, a monoclonal antibody that blocks CD276, which exhibited a strong synergistic effect in eliminating AML cells. This underscores cytoplasmic QKI localization as a key driver of venetoclax resistance through monocytic AML differentiation and highlights a promising immune-based strategy to overcome this resistance.