Unmasking the in vivo role of IGF1R in Chronic lymphocytic leukemia and identifying novel inhibitors for its function 2298900

Abstract Introduction Insulin-like growth factor 1 receptor (IGF1R) signaling is a key regulator of cellular anabolism and is critically implicated in the pathogenesis of various cancers, including Chronic Lymphocytic Leukemia (CLL). Previous in vitro studies have shown that pharmacological inhibition of IGF1R effectively induces CLL cell death. Our study aimed to understand the precise role of IGF1R in CLL development in vivo and to identify novel endogenous inhibitors of its function. Methods We generated a B cell-specific IGF1R knockout mouse model in the Eï•­-TCL1 transgenic background. In parallel, to identify novel endogenous inhibitors of IGF1R, we performed a large-scale screening of a human hemofiltrate peptide library, a valuable resource of bioactive molecules. Results Result: The deletion of IGF1R from B cells in the TCL1 mice led to a significantly reduced disease load compared to their undeleted TCL1 littermates reflecting that IGF1R actively enforces CLL development in vivo. Concurrently, screening of hemofiltrate library led to the identification and purification of a 14 kDa fragment derived from Insulin-like growth factor binding protein 6 (IGFBP6) that strongly inhibit IGF1-IGF1R interaction. Conclusion Our data collectively demonstrate the critical involvement of IGF1R in CLL progression and validate it as a therapeutic target. Furthermore, the identified IGFBP6 fragment represents a novel, endogenous agent for blocking IGF1R function and developing new CLL treatments. Funding Source CRC1279, German Research Foundation (DFG) Topic Categories Immune Mechanisms of Human Disease (HUM)