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ACUTE MYELOID LEUKEMIA

Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway

Abstract

Regulatory T cells (Tregs) could maintain the characteristics of stem cells and inhibit the differentiation of normal hematopoietic stem/progenitor cells. Recent studies have shown that Tregs, as an important component of acute myeloid leukemia (AML) microenvironments, can help AML cells to evade immune surveillance. However, their function in directly regulating the stemness of AML cells remains elusive. In this study, the increased stemness of AML cells promoted by Tregs was verified in vitro and in vivo. The cytokines released by Tregs were explored, the highly expressed anti-inflammatory cytokine IL10 was found, which could promote the stemness of AML cells through the activation of PI3K/AKT signal pathway. Moreover, disrupting the IL10/IL10R/PI3K/AKT signal in AML/ETO c-kitmut (A/Ec) leukemia mice could prolong the mice survival and reduce the stemness of A/Ec leukemia cells. Finally, it was confirmed in patient samples that the proportion of Tregs to leukemia stem cells (LSCs) was positively correlated, and in CD34+ primary AML cells, the activation of PI3K/AKT was stronger in patients with high Tregs’ infiltration. After rhIL10 treatment, primary AML cells showed increased activation of PI3K/AKT signaling. Therefore, blocking the interaction between Tregs and AML cells may be a new approach to target LSCs in AML treatment.

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Fig. 1: Tregs promoted the initiation of leukemia and shortened mice survival in vivo.
Fig. 2: Tregs increased the population of LSCs in AML cells in vitro.
Fig. 3: IL10 enhanced the stemness of AML cells.
Fig. 4: IL10R was required for promoting the stemness of leukemia cells by Tregs.
Fig. 5: PI3K/AKT signaling was required for promoting the stemness of leukemia cells by Tregs.
Fig. 6: Tregs promoted the expression of OCT4 and NANOG in AML cells.
Fig. 7: Blockade of IL10R or AKT activation could reduce the stemness of leukemia cells in vivo.
Fig. 8: IL10/IL10R/PI3K/AKT axis was existing in primary AML cells.

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Acknowledgements

This work was accepted as a poster abstract by the ASH Program Committee at the 59th Annual Meeting and Exposition, December 9-12, 2017, Atlanta, GA. This work was supported by grants from the National Natural Science Foundation of China (81700163, 82070170 and 81830005), Tianjin Municipal Science and Technology Commission Grant (20JCQNJC00290), and National Key Research and Development Program of China (2019YFA0110200).

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YXX conceived the study, performed most of the experiments, analyzed the data, and wrote the paper. JLM and YW helped perform some of the experiments. WZ helped the bioinformatics analysis. HYX and QR provided the study material. KJT and ZT supported administrative management. MW and JXW supervised the study and reviewed and approved the paper. All authors read and approved the final paper.

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Correspondence to Min Wang or Jianxiang Wang.

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Xu, Y., Mou, J., Wang, Y. et al. Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway. Leukemia 36, 403–415 (2022). https://doi.org/10.1038/s41375-021-01375-2

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