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

Abstract

Amino acid (AA) metabolism is involved in diverse cellular functions, including cell survival and growth, however it remains unclear how it regulates normal hematopoiesis versus leukemogenesis. Here, we report that knockout of Slc1a5 (ASCT2), a transporter of neutral AAs, 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 leukemia initiation and maintenance driven by the oncogene MLL-AF9 or Pten deficiency. Survival of leukemic mice is prolonged following Slc1a5 deletion, and pharmacological inhibition of ASCT2 also decreases leukemia development and progression in xenograft models of human acute myeloid leukemia. Mechanistically, loss of ASCT2 generates a global effect on cellular metabolism, disrupts leucine influx and mTOR signaling, and induces apoptosis in leukemic cells. Given the substantial difference in reliance on ASCT2-mediated AA metabolism between normal and malignant blood cells, this in vivo study suggests ASCT2 as a promising therapeutic target for the treatment of leukemia.

Metabolic Plasticity of Acute Myeloid Leukemia

“…However, the work overwhelmingly suggests that during the evolvement of the disease, AML cells considerably gain metabolic plasticity, which enables them to successfully infiltrate the various bone marrow niches, outgrow and annihilate normal hematopoiesis. Enhanced consumption of metabolites that are available at comfortable concentrations like glucose [29,30,47], glutamine [88,89,90,91,92,93] and FAs [121,125,126,127] is one gain that helps AML cells to divide more rapidly than their normal counterparts, and to evade the commonly encountered apoptotic stimuli. AML cells rewire the metabolic pathways so that they can optimally use the food without being at loss in energy or building blocks.…”

“…Similar to other cancers, plasma concentrations of glutamine in AML patients are considerably lower with concentrations below 0.3 mM, suggesting high glutamine consumption [88,89,90]. More direct evidence that AML cells are exquisitely dependent on exogenous glutamine came from data, where knockout of the high-affinity glutamine transporter SLC1A5 led to apoptosis of AML cell lines, and prevented tumor development in AML xenotransplantation and primary mouse AML models [91,92]. Several lines of evidence point towards a prominent role of glutamine in anaplerosis in AML.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Knockdown of ASCT2 diminishes mTORC1 activity and tumor growth [124][125][126][127][128]. Although the absence of Slc1A5 did not significantly diminish intracellular Gln or Glu levels, it disrupted influx of leucine and diminished levels of other amino acids crucial for redox homeostasis [128]. Leucine, an essential amino acid, is acquired by the cell through counter-transport with Gln [21].…”

A one-gate elevator mechanism for the human neutral amino acid transporter ASCT2

“…Over the past years, ASCT2 has increasingly gained attention as a potential target in anticancer therapy, as it is upregulated and linked to poor survival in melanoma, lung, breast, prostate, pancreatic, thyroid and colon cancer 5–10 . ASCT2 plays a role in cancer cell growth by providing glutamine as an alternative carbon source for the tricarboxylic acid (TCA) cycle, for fatty-acid production, and by contributing to the activation of the mammalian target of rapamycin complex (mTORC1) 11 . ASCT2 also acts as a receptor for several retroviruses 12 , and a recently determined structure 2 revealed unique extracellular antennae that likely form the required recognition platform 13 .…”