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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311644 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3) are a family of RNA-binding proteins that play an essential role in the development and disease by regulating mRNA stability and translation of critical regulators of cell division and metabolism. Genetic and chemical inhibition of these proteins slows down cancer cell proliferation, decreases invasiveness, and prolongs life span in a variety of animal models. The role of RNA-binding proteins in the induction of tissues’ immunogenicity is increasingly recognized, but, the impact of the IGF2BPs family of proteins on the induction of innate and adaptive immune responses in cancer is not fully understood. Here we report that downregulation of IGF2BP1, 2, and 3 expression facilitates the expression of interferon beta-stimulated genes. IGF2BP1 has a greater effect on interferon beta and gamma signalings compared to IGF2BP2 and IGF2BP3 paralogs. We demonstrate that knockdown or knockout of IGF2BP1, 2, and 3 significantly potentiates inhibition of cell growth induced by IFNβ and IFNγ. Mouse melanoma cells with Igf2bp knockouts demonstrate increased expression of MHC I (H-2) and induce intracellular Ifn-γ expression in syngeneic T-lymphocytes in vitro. Increased immunogenicity, associated with Igf2bp1 inhibition, “inflames” mouse melanoma tumors microenvironment in SM1/C57BL/6 and SW1/C3H mouse models measured by a two-fold increase of NK cells and tumor-associated myeloid cells. Finally, we demonstrate that the efficiency of anti-PD1 immunotherapy in the mouse melanoma model is significantly more efficient in tumors that lack Igf2bp1 expression. Our retrospective data analysis of immunotherapies in human melanoma patients indicates that high levels of IGF2BP1 and IGF2BP3 are associated with resistance to immunotherapies and poor prognosis. In summary, our study provides evidence of the role of IGF2BP proteins in regulating tumor immunogenicity and establishes those RBPs as immunotherapeutic targets in cancer.

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

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