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ACUTE MYELOID LEUKEMIA

circFAM193B interaction with PRMT6 regulates AML leukemia stem cells chemoresistance through altering the oxidative metabolism and lipid peroxidation

Leukemia volume 38, pages 1057–1071 (2024)Cite this article

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Abstract

Most forms of chemotherapy for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), as their underlying mechanisms remain unclear. Here, we have identified circFAM193B, which regulates the redox biology of LSCs and is associated with unfavorable outcomes in AML patients. In vitro and in vivo assays suggested that circFAM193B significantly inhibits LSCs chemotherapy resistance and AML progression. Knockdown circFAM193B enhances mitochondrial OXPHOS function and inhibits the accumulation of reactive oxygen species and lipid peroxidation mediated by chemotherapy, which protects AML cells from oxidative stress-induced cell death. Mechanistically, circFAM193B physically interacts with arginine methyltransferase PRMT6 catalytic domain and enhances the transcription efficiency of key lipid peroxidation factor ALOX15 by decreasing H3R2me2a modification. In summary, we have identified circFAM193B was downregulated in LSCs to promote the survival of LSC by modulating energy metabolism and the redox balance in the postchemotherapy persistence of LSC. Our studies provide a conceptual advance and biological insights regarding the drug resistance of LSCs via circRNA mediated PRMT6-deposited methylarginine signaling.

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Fig. 1: circFAM193B is downregulated in LSCs and characteristics of circFAM193B in AML cells.
Fig. 2: circFAM193B reduces the self-renewal, maintenance and chemo-resistance of LSCs.
Fig. 3: circFAM193B sensitizes AML cells to chemotherapy in vitro and in vivo.
Fig. 4: Knockdown of circFAM193B enhances metabolic reprogramming and protects AML cells from oxidative stress-induced cell death.
Fig. 5: circFAM193B suppresses AML by physically interacting with PRMT6 and inhibits the level of H3R2me2a.
Fig. 6: PRMT6 suppresses ALOX15 expression by catalyzing H3R2me2a modification and regulates AML stem cells by modulating lipid peroxidation.
Fig. 7: circFAM193B regulats AML via modulating energy metabolism and the redox balance.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank all participating patients, without whom continuous improvement in clinical care and growing scientific insights would not be possible. The authors acknowledge all contributing physicians, study nurses, and laboratories for their support in the trials.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 32241005, 82370173) and Natural Science Foundation of Shandong Province (Youth Program, ZR2023QH249).

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Authors and Affiliations

  1. Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, PR China

    Xinyu Yang, Jinting Liu, Wancheng Liu, Hanyang Wu, Yihong Wei, Xiaodong Guo, Hexiao Jia, Can Can, Dongmei Wang, Xiang Hu & Daoxin Ma

  2. Shandong Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, PR China

    Xinyu Yang, Jinting Liu, Wancheng Liu, Hanyang Wu, Yihong Wei, Xiaodong Guo, Hexiao Jia, Can Can, Dongmei Wang, Xiang Hu & Daoxin Ma

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Contributions

Professor DXM designed and funded the study. XYY performed this research. JTL, WCL, HYW and CC assisted with this research. YHW, XHJ and XDG analyzed the data. XH, DMW revised the manuscript accordingly. XYY wrote the manuscript.

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Correspondence to Daoxin Ma.

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The trials were approved by the respective ethics committees and were conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent, including the analysis of data. The studies were continuously monitored using clinical and medical monitoring.

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Yang, X., Liu, J., Liu, W. et al. circFAM193B interaction with PRMT6 regulates AML leukemia stem cells chemoresistance through altering the oxidative metabolism and lipid peroxidation. Leukemia 38, 1057–1071 (2024). https://doi.org/10.1038/s41375-024-02189-8

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