Work

Inhibition of TOX exerts anti-tumor effects in acute myeloid leukemia by upregulating IRF7 expression

Year: 2024

Type: article

Abstract: Thymocyte selection-associated high mobility group box protein (TOX) is regarded as a crucial transcription factor involved in T cell exhaustion in acute myeloid leukemia (AML). Previous studies have identified aberrant TOX expression as a major oncogenic driver in hematologic malignancies, indicating that TOX may potentially be both an immune biomarker and an immunotherapy target. However, due to heterogeneity in the distribution patterns of TOX and its correlation with clinical prognosis, the mechanism underlying TOX-mediated tumor immune responses remains unclear. In this study, we demonstrate that high TOX expression in AML patients is associated with poor prognosis, and TOX overexpression promotes AML cell proliferation and restricts apoptosis. In vitro TOX inhibition promoted the apoptosis of AML cells, suppressed cell viability, and induced cell cycle arrest in the G0/G1 phase. Moreover, TOX knockdown could reduce tumor burden in vivo in immunodeficient mice and prolong their survival. Furthermore, the anti-AML effects of inhibiting TOX may act through activation of the IFN-α signal pathway and upregulating IRF7 expression. In summary, we report for the first time that TOX knockdown exerts powerful anti-tumor effects in AML. These findings will provide a theoretical basis for targeted therapy in AML patients. • TOX overexpression promoted AML cell proliferation and restricted apoptosis. • TOX inhibition promoted the apoptosis of AML cells, suppressed cell viability, and induced cell cycle arrest in the G0/G1 phase. • Knockdown of TOX could reduce the tumor burden in immunodeficient mice and prolong survival time in vivo. • The anti-AML effects of TOX inhibition may work through activation of the IFN-α pathway and upregulation of IRF7 expression.

Source: European Journal of Pharmacology

DOI: 10.1016/j.ejphar.2024.177163