Author:
Stanulović Vesna S.,Reed Michelle A.C.,Patani Hemalvi,Potluri Sandeep,Georgiadou Eleni,Roberts Jennie,Sarkar Sovan,Pratt Guy,Jones Alan M.,Günther Ulrich,Ludwig Christian,Hoogenkamp Maarten
Abstract
SummaryT-cell acute lymphoblastic leukaemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients relapse and die from the disease. To improve patient outcome new drugs are needed. With the aim to identify new therapeutic targets, we integrated transcriptomics and metabolomics data, including live-cell NMR-spectroscopy, of cell lines and patient samples. We found that T-ALL cells have limited energy availability, resulting in active AMPK-signalling and reduced autophagy. Despite this, mTOR kinase remains active and essential for glutamine-uptake that fuels rapid proliferation. Glutamine fuels aspartate synthesis and together they supply three nitrogen atoms in purines and all atoms but one carbon in pyrimidine rings. We show that EAAT1, a glutamate-aspartate transporter normally only expressed in the CNS, is crucial for glutamine conversion to nucleotides and that T-ALL cell proliferation depends on EAAT1 function, identifying it as a target for T-ALL treatment. Finally, we performed anin silicoscreen and identified a novel EAAT1-specific allosteric inhibitor.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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