Translational oncology · 2026
ATO alleviates T-cell immunosuppression by inducing apoptosis-associated secretion of IL-2 in FLT3-ITD-mutated acute myeloid leukemia.
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Ou Yiqing, Hao Guojun, Wu Yan, Guo Ziwen, He Xin, Niu Xiaomin
Аннотация
BACKGROUND: Arsenic trioxide (ATO) is effective against FLT3-mutant acute promyelocytic leukemia (APL), but its role in non-APL FLT3-ITD-mutant acute myeloid leukemia (AML) remains unclear. This study aims to investigate the mechanistic impact of ATO on FLT3-ITD-mutated AML cells.
METHODS: This study utilized the CCK-8 assay, Wright-Giemsa staining, flow cytometry, Western blotting, and colorimetric assays to assess the effects of ATO on cell viability, cell morphology, apoptosis, Ki67 expression, reactive oxygen species (ROS), IL-2 levels, expression of apoptosis-related proteins, and LDH release in MV4-11 and HL-60 cells. Further validation was performed using NAC, PD98059 and LM22B-10. Following T-cell co-culture experiments, interferon-γ (IFN-γ) and granzyme B (GZMB) levels were measured. Differences in IL-2 expression were validated in primary cells from patients with AML.
RESULTS: Compared to HL-60 cells, ATO-treated FLT3-ITD-mutated MV4-11 cells exhibited lower IC50, reduced Ki67 expression, and elevated LDH levels. ATO induced dose- and time-dependent apoptosis in MV4-11 cells, accompanied by increased Cleaved Caspase-3 expression and Bax/Bcl-2 ratio. NAC attenuated ATO-induced ROS accumulation and apoptosis. ATO suppressed extracellular signal-regulated kinase (ERK) phosphorylation in a concentration-dependent manner, which was reversed by LM22B-10 but exacerbated by PD98059. Additionally, ATO enhanced IL-2 secretion in MV4-11 cells, and their conditioned medium elevated IFN-γ and GZMB levels in CD4+ and CD8+ T cells. Similar IL-2 upregulation was observed in primary cells from FLT3-ITD+ AML patients.
CONCLUSIONS: ATO triggers apoptosis in FLT3-ITD-mutated AML cells via ROS/ERK signaling and modulates T-cell activity through IL-2 secretion, suggesting a dual role in tumor suppression and immune regulation.
SIGNIFICANCE: This study confirms that ATO is a potential candidate drug for the treatment of FLT3-ITD-mutant AML and provides mechanistic insights into its cytotoxic and immunomodulatory functions.
METHODS: This study utilized the CCK-8 assay, Wright-Giemsa staining, flow cytometry, Western blotting, and colorimetric assays to assess the effects of ATO on cell viability, cell morphology, apoptosis, Ki67 expression, reactive oxygen species (ROS), IL-2 levels, expression of apoptosis-related proteins, and LDH release in MV4-11 and HL-60 cells. Further validation was performed using NAC, PD98059 and LM22B-10. Following T-cell co-culture experiments, interferon-γ (IFN-γ) and granzyme B (GZMB) levels were measured. Differences in IL-2 expression were validated in primary cells from patients with AML.
RESULTS: Compared to HL-60 cells, ATO-treated FLT3-ITD-mutated MV4-11 cells exhibited lower IC50, reduced Ki67 expression, and elevated LDH levels. ATO induced dose- and time-dependent apoptosis in MV4-11 cells, accompanied by increased Cleaved Caspase-3 expression and Bax/Bcl-2 ratio. NAC attenuated ATO-induced ROS accumulation and apoptosis. ATO suppressed extracellular signal-regulated kinase (ERK) phosphorylation in a concentration-dependent manner, which was reversed by LM22B-10 but exacerbated by PD98059. Additionally, ATO enhanced IL-2 secretion in MV4-11 cells, and their conditioned medium elevated IFN-γ and GZMB levels in CD4+ and CD8+ T cells. Similar IL-2 upregulation was observed in primary cells from FLT3-ITD+ AML patients.
CONCLUSIONS: ATO triggers apoptosis in FLT3-ITD-mutated AML cells via ROS/ERK signaling and modulates T-cell activity through IL-2 secretion, suggesting a dual role in tumor suppression and immune regulation.
SIGNIFICANCE: This study confirms that ATO is a potential candidate drug for the treatment of FLT3-ITD-mutant AML and provides mechanistic insights into its cytotoxic and immunomodulatory functions.