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

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@techreport{1840907b08a14d43accaeef9abef441c,
title = "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",
abstract = "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 down-regulated mTOR-signalling and reduced autophagy. Despite this, mTOR kinase remains active and essential for the glutamine-uptake and rapid proliferation, as glutamine supplies three nitrogen atoms in purines and all atoms but one carbon in pyrimidines. 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.",
author = "Stanulovi{\'c}, {Vesna S.} and Reed, {Michelle A.C.} and Hemalvi Patani and Sandeep Potluri and Eleni Georgiadou and Jennie Roberts and Sovan Sarkar and Guy Pratt and Jones, {Alan M.} and Ulrich G{\"u}nther and Christian Ludwig and Maarten Hoogenkamp",
year = "2020",
month = feb,
day = "25",
doi = "10.1101/2020.02.08.939694",
language = "English",
publisher = "bioRxiv",
type = "WorkingPaper",
institution = "bioRxiv",

}

RIS

TY - UNPB

T1 - 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

AU - Stanulović, Vesna S.

AU - Reed, Michelle A.C.

AU - Patani, Hemalvi

AU - Potluri, Sandeep

AU - Georgiadou, Eleni

AU - Roberts, Jennie

AU - Sarkar, Sovan

AU - Pratt, Guy

AU - Jones, Alan M.

AU - Günther, Ulrich

AU - Ludwig, Christian

AU - Hoogenkamp, Maarten

PY - 2020/2/25

Y1 - 2020/2/25

N2 - 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 down-regulated mTOR-signalling and reduced autophagy. Despite this, mTOR kinase remains active and essential for the glutamine-uptake and rapid proliferation, as glutamine supplies three nitrogen atoms in purines and all atoms but one carbon in pyrimidines. 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.

AB - 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 down-regulated mTOR-signalling and reduced autophagy. Despite this, mTOR kinase remains active and essential for the glutamine-uptake and rapid proliferation, as glutamine supplies three nitrogen atoms in purines and all atoms but one carbon in pyrimidines. 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.

U2 - 10.1101/2020.02.08.939694

DO - 10.1101/2020.02.08.939694

M3 - Working paper

BT - 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

PB - bioRxiv

ER -