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

Oncogene volume 42, pages 3657–3669 (2023)Cite this article

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Abstract

Conventional therapies for acute myeloid leukemia (AML) often fail to eliminate the disease-initiating leukemia stem cell (LSC) population, leading to disease relapse. Interferon-γ (IFN-γ) is a known inflammatory cytokine that promotes antitumor responses. Here, we found that low serum IFN-γ 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 μg/day) of IFN-γ exerted an anti-AML effect, while low doses (0.01–0.05 μg/day) of IFN-γ 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-γ 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-γ and IFNGR1 in AML stemness and showed that targeting IFNGR1 is a strategy to decrease stemness and increase differentiation in relapsed AML patients.

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Fig. 1: Low levels of IFN-γ and high levels of IFNGR1 are associated with a high percentage of LSCs and poor prognosis in AML patients.
Fig. 2: IFN-γ delays AML progression at high doses but promotes AML development at low doses in mice.
Fig. 3: Low doses of IFN-γ promote AML stemness in vitro.
Fig. 4: Low doses of IFN-γ promote AML development and maintenance in mice.
Fig. 5: Activation of the PI3K–AKT and PPARγ pathways contributes to the effect of low-dose IFN-γ on LSCs in AML.
Fig. 6: Targeting IFNGR1 by shRNA induces AML stem cell differentiation and delays AML progression.
Fig. 7: Neutralization of IFNGR1 by antibody reduces AML stem cell properties and prevents AML progression induced by low doses of IFN-γ in mice.

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Data availability

The raw data of RNA sequencing were deposited at National Center for Biotechnology Information (NCBI) under BioProject nos. PRJNA992770 and PRJNA757222. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Acknowledgements

We thank our patient volunteers for participation in the study. We would like to thank Professor Tao Cheng (Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin) for providing MLL-AF9 murine cells.

Funding

This work was supported by the National Natural Science Foundation of China (82100155, 81991511, 81991510), and the China Postdoctoral Science Foundation (2022M720060).

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  1. These authors contributed equally: Xiaoling Xie, Wuju Zhang.

Authors and Affiliations

  1. Department of Hematology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, China

    Xiaoling Xie, Xuan Zhou, Binyan Xu, Hao Wang, Yingqi Qiu, Yuxing Hu, Honghao Zhang & Yuhua Li

  2. Central Laboratory, The Fifth Affiliated Hospital, Southern Medical University, 510910, Guangzhou, China

    Wuju Zhang

  3. Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China

    Bin Guo, Zhixin Ye, Le Hu & Xiaochun Bai

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Contributions

XLX, XCB, and YHL conceived the project, guided the research, and wrote the paper; XLX, WJZ, HW, YXH, BYX, and YQQ performed the experiments and analyzed the data; XZ, BYX, and YHL provided primary leukemia patient samples; XLX, WJZ, ZXY, BG, HHZ, and LH performed mouse experiments and collected the data.

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Correspondence to Xiaoling Xie, Yuhua Li or Xiaochun Bai.

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Xie, X., Zhang, W., Zhou, X. et al. Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia. Oncogene 42, 3657–3669 (2023). https://doi.org/10.1038/s41388-023-02874-5

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