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Targeted therapies, such as the BCL-2 inhibitor venetoclax, have expanded the treatment options for patients with acute myeloid leukemia (AML), but survival remains poor because of drug resistance and disease relapse. We found that the translation initiation factor , which unwinds complex messenger RNA structures in the 5' untranslated region (UTR) of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells relative to healthy hematopoietic stem and progenitor cells. Inhibition of eukaryotic initiation factor 4A (eIF4A) with the first-in-class small molecule zotatifin reduces the translation efficiency of transcripts related to the cell cycle and oncogenic signaling via the PI3K/AKT/mTOR pathway, as shown by ribosome profiling and gene set enrichment analysis. Western blot analysis corroborated these findings and demonstrated the 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); however, its effect in primary healthy BM is limited. Using 3 in vivo xenograft models derived from patients with relapsed/refractory AML, the combination significantly suppressed the 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.