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Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression

Nature Metabolismvolume 1pages390403 (2019) | Download Citation

Abstract

Amino acid metabolism is involved in diverse cellular functions, including cell survival and growth; however, it remains unclear how it regulates normal haematopoiesis versus leukaemogenesis. Here, we report that knockout of solute carrier family 1 member 5 (Slc1a5/ASCT2), a transporter of neutral amino acids, especially glutamine, results in mild-to-moderate defects in bone marrow and mature blood cell development under steady-state conditions. In contrast, constitutive or induced deletion of Slc1a5 decreases leukaemia initiation and maintenance driven by oncogene MLL-AF9 or phosphatase and tensin homologue (Pten) deficiency. Survival of leukaemic mice is prolonged following Slc1a5 deletion, and pharmacological inhibition of ASCT2 also decreases leukaemia development and progression in xenograft models of human acute myeloid leukaemia. Mechanistically, loss of ASCT2 generates a global effect on cellular metabolism, disrupts leucine (Leu) influx and mechanistic target of rapamycin (mTOR) signalling, and induces apoptosis in leukaemic cells. Given the substantial difference in reliance on ASCT2-mediated amino acid metabolism between normal and malignant blood cells, this in vivo study suggests ASCT2 as a promising therapeutic target for the treatment of leukaemia.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. The Reporting Summary for this article is available as a Supplementary Information file.

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Acknowledgements

This work was supported by the National Institutes of Health grant nos. DK092722 and HL130995 (to C.K.Q).

Author information

Affiliations

  1. Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    • Fang Ni
    • , Wen-Mei Yu
    • , Zhiguo Li
    • , Douglas K. Graham
    •  & Cheng-Kui Qu
  2. Department of Hematology/Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    • Lingtao Jin
    •  & Sumin Kang
  3. Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    • Michael R. Rossi
  4. Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    • Shiyong Li
  5. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    • Hal E. Broxmeyer

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Contributions

F.N. and W.M.Y. generated and characterized the haematopoietic cell development in Slc1a5 global and conditional knockout mice, set up the mouse leukaemia models and xenograft models of human AML and analysed leukaemia development/progression. F.N. also performed metabolic assays and rescue experiments. Z.L. performed the immunoblot analyses. L.J. performed the metabolite analyses. D.K.G. and S.L. provided patient specimens and discussed the work. M.R.R. and L.J. conducted TCGA and TARGET database mining and performed the correlation analyses. S.K. and H.E.B. provided critical advice on experimental design and interpretation of the data, and edited the manuscript. C.K.Q. designed the experiments and directed the entire project. F.N. and C.K.Q. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Cheng-Kui Qu.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–13 and Supplementary Table 2

  2. Reporting Summary

  3. Supplementary Table 1

    Metabolomic analysis data of ASCT2-deleted and ASCT2-undeleted Pten-deficient Lin– leukemic cells

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DOI

https://doi.org/10.1038/s42255-019-0039-6