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

Fang Ni, Wen Mei Yu, Zhiguo Li, Douglas K. Graham, Lingtao Jin, Sumin Kang, Michael R. Rossi, Shiyong Li, Hal E. Broxmeyer, Cheng Kui Qu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)390-403
Number of pages14
JournalNature Metabolism
Volume1
Issue number3
DOIs
StatePublished - Mar 1 2019

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Leukemia
Amino Acids
Blood Cells
Neutral Amino Acid Transport Systems
Hematopoiesis
Sirolimus
Glutamine
Oncogenes
Phosphoric Monoester Hydrolases
Heterografts
Acute Myeloid Leukemia
Leucine
Cell Survival
Bone Marrow
Maintenance
Pharmacology
Apoptosis
Growth
Therapeutics
Inhibition (Psychology)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

Cite this

Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression. / Ni, Fang; Yu, Wen Mei; Li, Zhiguo; Graham, Douglas K.; Jin, Lingtao; Kang, Sumin; Rossi, Michael R.; Li, Shiyong; Broxmeyer, Hal E.; Qu, Cheng Kui.

In: Nature Metabolism, Vol. 1, No. 3, 01.03.2019, p. 390-403.

Research output: Contribution to journalArticle

Ni, Fang ; Yu, Wen Mei ; Li, Zhiguo ; Graham, Douglas K. ; Jin, Lingtao ; Kang, Sumin ; Rossi, Michael R. ; Li, Shiyong ; Broxmeyer, Hal E. ; Qu, Cheng Kui. / Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression. In: Nature Metabolism. 2019 ; Vol. 1, No. 3. pp. 390-403.
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