Therapeutic targeting of an oncogenic translational program in AML

PROJECT SUMMARY CBFβ-SMMHC is the driver oncogene in acute myeloid leukemia (AML) with the chromosome inversion inv(16)(p13q22). CBFβ-SMMHC induces AML by sequestering RUNX1, the transcription factor that plays an important role in normal hematopoiesis. Adult inv(16) AML patients present poor clinical outcomes - 30-40% of these patients relapse and die from the disease. This suggests developing better therapeutic strategies for treating inv(16) AML is critical. We recently developed a small molecule inhibitor, AI-10-49, which specifically disrupts CBFβ-SMMHC binding to RUNX1. AI-10-49 treatment induced leukemic cell apoptosis in human primary inv(16) AML cells and enhanced survival in an inv(16) mouse model. AI-10-49 is the first targeted therapy for inv(16) AML and is under development as an anti-leukemic drug. In a recent study, we explored the mechanism of action of AI-10-49. We found that AI-10-49-induced cell death is partly mediated by inhibition of the eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) in inv(16) AML cells. eIF4G1 inhibition leads to apoptosis in inv(16) AML cells, indicating eIF4G1 as a therapeutic target. We also found that reactivation of eIF4G1 is a major source of AI-10-49 resistance in inv(16) AML cells, and eIF4G1 inhibition by the small molecule inhibitor SBI- 756 can overcome drug resistance in inv(16) AML cells. Our results provide proof-of-concept for testing eIF4G1 inhibitors in combination with AI-10-49 to overcome drug resistance during treatment of inv(16) AML. Our data suggest that overexpression of eIF4G1 by CBFβ-SMMHC is a critical step in inv(16) AML transformation. We hypothesize that CBFβ-SMMHC activates eIF4G1 in inv(16) AML, altering protein synthesis and rewiring the AML proteome, which, in turn, promotes leukemogenesis and reactivation of eIF4G1, contributing to AI-10-49 resistance. We will test this hypothesis by i) characterizing the therapeutic value of SBI-756, an eIF4G1 small molecule inhibitor, in inv(16) AML cell survival using a CBFβ-SMMHC genetic mouse model and an inv(16) AML patient-derived xenograft model, and ii) defining the mechanisms of action of eIF4G1 in inv(16) AML.