The bone marrow (BM) microenvironment in acute myeloid leukemia (AML) shields leukemic cells from chemotherapy, fostering disease recurrence and progression. This study investigated the impact of eukaryotic initiation factor 4E (eIF4E) in AML progression and chemosensitivity, highlighting stroma-dependent chemoprotection mechanisms to develop potential microenvironment-directed therapies. The GEO dataset was analyzed for the relationship between eIF4E mRNA expression and clinical characteristics in AML patients. We established the stromal-AML co-culture system (HS-5 cells with U937, HL-60, and primary AML cells) and the humanized mouse AML model to systematically evaluate eIF4E's role in modulating homoharringtonine (HHT) and arsenic trioxide (ATO) cytotoxicity within the leukemic microenvironment. Elevated eIF4E expression was significantly correlated with poor prognosis in AML patients. After co-culture with HS-5 cells, the sensitivity of AML cells to HHT/ATO was reduced considerably. More importantly, we observed markedly increased levels of phosphorylated eIF4E in AML cells after co-culture, concomitant with elevated expression of Mcl-1 and p-4E-BP1Thr37/Thr46. In contrast, combined HHT/ATO treatment significantly suppressed the 4E-BP1-eIF4E-Mcl-1 axis in both stromal co-culture and humanized AML mouse models. Genetic perturbation studies demonstrated that eIF4E knockdown sensitized AML cells to HHT/ATO, whereas its overexpression conferred therapeutic resistance. eIF4E may play an essential role in mediating the cytotoxic effects of HHT and ATO, representing a novel therapeutic target in AML.
Chen et al. (Thu,) studied this question.