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Proliferation and Survival of T-cell Acute Lymphoblastic Leukaemia Depends on mTOR-regulated Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides

Vesna S. Stanulović, Michelle A.C. Reed, Hemalvi Patani, Sandeep Potluri, Eleni Georgiadou, Jennie Roberts, Sovan Sarkar, Guy Pratt, Alan M. Jones, Ulrich Günther, Christian Ludwig, Maarten Hoogenkamp
doi: https://doi.org/10.1101/2020.02.08.939694
Vesna S. Stanulović
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Michelle A.C. Reed
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Hemalvi Patani
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
5Bart’s Cancer Institute, Queen Mary University of London, London, Greater London, EC1M 6BQ, United Kingdom
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Sandeep Potluri
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Eleni Georgiadou
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
6Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, Greater London, W12 0NN, United Kingdom
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Jennie Roberts
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Sovan Sarkar
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Guy Pratt
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
2Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, West Midlands, B15 2GW, Birmingham, United Kingdom
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Alan M. Jones
3School of Pharmacy, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Ulrich Günther
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Christian Ludwig
4Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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Maarten Hoogenkamp
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, West Midlands, B15 2TT, United Kingdom
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  • For correspondence: m.hoogenkamp@bham.ac.uk
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Summary

T-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 an in silico screen and identified a novel EAAT1-specific allosteric inhibitor.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 25, 2020.
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Proliferation and Survival of T-cell Acute Lymphoblastic Leukaemia Depends on mTOR-regulated Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides
Vesna S. Stanulović, Michelle A.C. Reed, Hemalvi Patani, Sandeep Potluri, Eleni Georgiadou, Jennie Roberts, Sovan Sarkar, Guy Pratt, Alan M. Jones, Ulrich Günther, Christian Ludwig, Maarten Hoogenkamp
bioRxiv 2020.02.08.939694; doi: https://doi.org/10.1101/2020.02.08.939694
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Proliferation and Survival of T-cell Acute Lymphoblastic Leukaemia Depends on mTOR-regulated Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides
Vesna S. Stanulović, Michelle A.C. Reed, Hemalvi Patani, Sandeep Potluri, Eleni Georgiadou, Jennie Roberts, Sovan Sarkar, Guy Pratt, Alan M. Jones, Ulrich Günther, Christian Ludwig, Maarten Hoogenkamp
bioRxiv 2020.02.08.939694; doi: https://doi.org/10.1101/2020.02.08.939694

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