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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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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This work was supported by the National Institutes of Health grant nos. DK092722 and HL130995 (to C.K.Q).
The authors declare no competing interests.
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Ni, F., Yu, WM., Li, Z. et al. Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression. Nat Metab 1, 390–403 (2019). https://doi.org/10.1038/s42255-019-0039-6
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