Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia

作者：Xie, Xiaoling^*; Zhang, Wuju; Zhou, Xuan; Xu, Binyan; Wang, Hao; Qiu, Yingqi; Hu, Yuxing; Guo, Bin; Ye, Zhixin; Hu, Le; Zhang, Honghao; Li, Yuhua^*; Bai, Xiaochun^*

来源：Oncogene, 2023, 42(50): 3657-3669.

DOI：10.1038/s41388-023-02874-5

• INTERFERON-GAMMA
• INDUCTION
• GROWTH
• TRANSFORMATION
• PROLIFERATION
• INHIBITION
• PROGENITOR
• THERAPY
• MURINE
• ALPHA

Conventional therapies for acute myeloid leukemia (AML) often fail to eliminate the disease-initiating leukemia stem cell (LSC) population, leading to disease relapse. Interferon-gamma (IFN-gamma) is a known inflammatory cytokine that promotes antitumor responses. Here, we found that low serum IFN-gamma levels correlated with a higher percentage of LSCs and greater relapse incidence in AML patients. Furthermore, IFNGR1 was overexpressed in relapsed patients with AML and associated with a poor prognosis. We showed that high doses (5-10 mu g/day) of IFN-gamma exerted an anti-AML effect, while low doses (0.01-0.05 mu g/day) of IFN-gamma accelerated AML development and supported LSC self-renewal in patient-derived AML-LSCs and in an LSC-enriched MLL-AF9-driven mouse model. Importantly, targeting the IFN-gamma receptor IFNGR1 by using lentiviral shRNAs or neutralizing antibodies induced AML differentiation and delayed leukemogenesis in vitro and in mice. Overall, we uncovered essential roles for IFN-gamma and IFNGR1 in AML stemness and showed that targeting IFNGR1 is a strategy to decrease stemness and increase differentiation in relapsed AML patients.

• 单位
  南方医科大学; 5