Abstract Acute myeloid leukemia (AML) is an aggressive blood malignancy with a dismal 5-year survival rate below 30%. Dysregulation of mRNA translation is a hallmark and a driver of tumorigenesis, including leukemogenesis. However, the precise contributions of translation factors to AML pathogenesis and their potential as therapeutic targets remain poorly understood. Here, we identify eukaryotic translation initiation factor 4A1 (eIF4A1) as a promising vulnerability of AML; genetic depletion or pharmacological inhibition of eIF4A1 markedly suppresses AML initiation and progression via reprogramming amino acid metabolism. Through unbiased multi-omics analysis, we identified eIF4A1 as the most highly expressed translation factor in AML. Notably, eIF4A1 expression was significantly elevated in AML cells and patient samples compared to healthy controls. eIF4A1 knockout (KO) dramatically inhibited AML cell proliferation, suppressed mitochondrial respiration, and reduced global translation intensity in vitro and substantially delayed AML progression in vivo. While eIF4A1 is traditionally studied within the cap-binding eIF4F complex, our other findings uncover a novel eIF4F complex-independent mechanism. BioID-MS assays, coupled with the validation of PLA assays and co-IP assays, revealed the robust RNA independent proximity of eIF4A1 and mRNA stabilizer Y-box binding protein 1 (YB-1). Integrative RNA-seq and proteomics demonstrated phosphoglycerate dehydrogenase (PHGDH) as a functionally essential target of eIF4A1. Moreover, metabolic profiling combined with isotope tracing (13C) orthogonally confirmed the crucial role of eIF4A1 in rewiring de novo serine metabolism, in which PHGDH serves as the rate-limiting enzyme. Gene specific CLIP-qPCR verified the direct binding of both eIF4A1 and YB-1 to PHGDH mRNA. Furthermore, the KO of either eIF4A1 or YB-1 accelerated PHGDH mRNA decay. Collectively, these findings suggest an eIF4F-independent mechanism of eIF4A1: eIF4A1 cooperates with YB-1, stabilized PHGDH mRNA and reprogrammed amino acid metabolism in AML. Zotatifin, an FDA-approved eIF4A1 inhibitor, administered intraperitoneally (0.5 mg/kg; twice weekly for five weeks), dramatically reduced the leukemia burden and significantly prolonged survival of AML mouse models in vivo (immunodeficient xenograft model: 63 vs. 150 days median survival for PBS vs. Zotatifin, P = 0.0006; immunocompetent bone marrow transplantation model: 40 vs. 75 days, P = 0.001). Moreover, Zotatifin demonstrated strong synergistic activity with the YB-1 inhibitor SU056 in eradicating AML both in vitro and in vivo (P 0.0001), primarily by disrupting amino acid biosynthesis. Overall, our findings identify eIF4A1 as a key regulator of AML pathogenesis and metabolic homeostasis. Targeting eIF4A1, particularly with Zotatifin, represents a promising therapeutic strategy for AML. Citation Format: Xiaoxu Zhang, Honghai Zhang, Lei Dong, Alexandra Huang, Xueer Wang, Lili Ren, Hongjie Bi, Seán O’Leary, Rui Su. Pharmacological inhibition of eIF4A1 suppresses leukemogenesis via specifically rewiring amino acid biosynthesis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4037.
Zhang et al. (Fri,) studied this question.
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