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Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma

Oncogene volume 41, pages 2287–2302 (2022)Cite this article

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Abstract

RORγt is a master regulator of Th17 cells. Despite evidence linking RORγt deficiency/inhibition with metastatic thymic T cell lymphomas, the role of RORγt in lymphoma metabolism is unknown. Chronic alcohol consumption plays a causal role in many human cancers. The risk of T cell lymphoma remains unclear in humans with alcohol use disorders (AUD) after chronic RORγt inhibition. Here we demonstrated that alcohol consumption accelerates RORγt deficiency-induced lymphomagenesis. Loss of RORγt signaling in the thymus promotes aerobic glycolysis and glutaminolysis and increases allocation of glutamine carbon into lipids. Importantly, alcohol consumption results in a shift from aerobic glycolysis to glutaminolysis. Both RORγt deficiency- and alcohol-induced metabolic alterations are mediated by c-Myc, as silencing of c-Myc decreases the effects of alcohol consumption and RORγt deficiency on glutaminolysis, biosynthesis, and tumor growth in vivo. The ethanol-mediated c-Myc activation coupled with increased glutaminolysis underscore the critical role of RORγt-Myc signaling and translation in lymphoma.

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Fig. 1: Impact of alcohol consumption on the development of RORγt deficiency-driven thymic lymphoma.
Fig. 2: Transcriptomic profiling identifies metabolic reprogramming as a hallmark of RORγt deficiency and alcohol consumption.
Fig. 3: RORγt regulates mitochondrial and metabolic phenotypes of thymocytes.
Fig. 4: RORγt and alcohol consumption regulate aerobic glycolysis in thymocytes.
Fig. 5: RORγt deficiency cooperates with alcohol consumption to promote glutaminolysis.
Fig. 6: Inhibition of RORγt promotes glutamine-dependent biosynthesis in lymphoma under glucose insufficient condition.
Fig. 7: c-Myc mediates the effects of RORγt loss on glutaminolysis and biosynthesis.
Fig. 8: c-Myc mediates the metabolic and tumorigenic effects induced by RORγt loss with alcohol consumption.

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Acknowledgements

This work was supported by grants from the NIH R21AA025724, R21AI128206, R21AI159194 and R01 DK115406 (ZD), and NIH P50AA024337, P20GM113226, (CJM). We thank Dr. J. Ainsworth for editorial assistance.

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  1. These authors contributed equally: Rui Sun, Chao Lei.

Authors and Affiliations

  1. Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA

    Rui Sun, Chao Lei, Liang Chen, Jun Yan & Zhongbin Deng

  2. Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, China

    Rui Sun

  3. Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Rui Sun, Chao Lei, Liang Chen, Jun Yan & Zhongbin Deng

  4. Department of Chemistry, University of Louisville, Louisville, KY, USA

    Liqing He & Xiang Zhang

  5. Department of Radiology, University of Louisville, Louisville, KY, USA

    Haixun Guo

  6. Alcohol Research Center, University of Louisville, Louisville, KY, USA

    Xiang Zhang, Wenke Feng, Craig J. McClain & Zhongbin Deng

  7. Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA

    Xiang Zhang, Wenke Feng, Craig J. McClain & Zhongbin Deng

  8. Department of Medicine, University of Louisville, Louisville, KY, USA

    Wenke Feng & Craig J. McClain

  9. Robley Rex VA Medical Center, Louisville, KY, USA

    Craig J. McClain

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Contributions

ZD and RS designed the research, analyzed and interpreted data, and drafted the manuscript; RS, CL, LC, LH, and HG performed experiments and interpreted data; and WF, XZ, JY, and CJM interpreted the findings and reviewed the manuscript.

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Correspondence to Zhongbin Deng.

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Sun, R., Lei, C., Chen, L. et al. Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma. Oncogene 41, 2287–2302 (2022). https://doi.org/10.1038/s41388-022-02257-2

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