Synergistic Targeting of eIF4A - Mediated Translation Initiation and Apoptosis in Acute Myeloid Leukemia
Targeted therapies like the BCL-2 inhibitor Venetoclax have expanded treatment options for acute myeloid leukemia (AML) patients, but survival remains poor due to drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex mRNA structures in the 5' UTR of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells relative to healthy hematopoietic stem and progenitor cells (HSPCs). Inhibition of eIF4A with the first-in-class small molecule Zotatifin reduces translation efficiency of transcripts related to the cell cycle and oncogenic signaling via PI3K/AKT/mTOR pathway, as shown by ribosome profiling and gene set enrichment analysis. Western blot analysis corroborated these findings, demonstrating downregulation of AKT, STAT-5, and MCL-1, factors implicated in resistance to Venetoclax-based regimens. The combination of Zotatifin and Venetoclax synergistically kills AML cells in vitro and induces apoptosis across AML genotypes, with selectivity toward progenitor-like cells in primary AML bone marrow (BM), whereas its effect in primary healthy BM is limited. Using three in vivo relapsed and refractory AML patient-derived xenograft models, the combination significantly suppressed tumor burden and prolonged survival. These results support eIF4A-mediated protein translation as a therapeutic target in AML and highlight the potential of Zotatifin and Venetoclax in relapsed/refractory disease. Overall design: MOLM-13 cells were treated with DMSO (control) or the eIF4A inhibitor Zotatifin for four hours. Then cells were harvested for RNA-seq and Ribo-sequencing.