Oncofetal RNA-binding proteins IGF2BP suppress innate immune signaling pathways in leukemia stem cells [ATAC-seq]

Activation of innate inflammatory signaling and tumor-specific antigen presentation in cancer cells provides a foundation for anti-cancer immunotherapies. Here, we show that Insulin-like Growth Factor 2 mRNA-Binding Proteins (IGF2BP1, IGF2BP2, and IGF2BP3), which are upregulated across various human malignancies, including acute myeloid leukemia (AML), suppress the activity of RNA-sensing pattern recognition receptors and downstream ISRE- and NF-κB-driven transcription. IGF2BPs exert a strong inhibitory effect on RIG-I signaling. This suppression is most pronounced when all three paralogs are co-expressed, particularly in embryonic-like hematoendothelial and leukemia stem cells and is at least partly mediated through IGF2BP-dependent regulation of negative regulators of immune signaling. Genetic and pharmacological inhibition of IGF2BPs activates innate immune signaling and induces MHC class I gene expression in AML, highlighting a promising strategy for RIG-I- and TLR-based cancer immunotherapies.