Hematology (Amsterdam, Netherlands) · 2025
Role of eIF4E in mediating cytotoxic effect of HHT and ATO on AML cells in bone marrow microenvironment.
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Chen Ping, Li Xiaojing, Zhan Weiwu, Lin Kaiting, Lin Bicun, Lin Xiaobin, Huang Meijuan
Аннотация
BACKGROUND: The bone marrow (BM) microenvironment in acute myeloid leukemia (AML) shields leukemic cells from chemotherapy, fostering disease recurrence and progression.
OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: eIF4E may play an essential role in mediating the cytotoxic effects of HHT and ATO, representing a novel therapeutic target in AML.
OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: eIF4E may play an essential role in mediating the cytotoxic effects of HHT and ATO, representing a novel therapeutic target in AML.