RT Journal Article
SR Electronic
T1 Survival and Proliferation of T-cell Acute Lymphoblastic Leukaemia Depends on mTOR-regulated Glutamine Uptake and EAAT1 Activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.08.939694
DO 10.1101/2020.02.08.939694
A1 Vesna S. Stanulović
A1 Michelle A.C. Reed
A1 Hemalvi Patani
A1 Sandeep Potluri
A1 Eleni Georgiadou
A1 Jennie Roberts
A1 Sovan Sarkar
A1 Guy Pratt
A1 Alan M. Jones
A1 Ulrich Günther
A1 Christian Ludwig
A1 Maarten Hoogenkamp
YR 2020
UL http://biorxiv.org/content/early/2020/02/10/2020.02.08.939694.abstract
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.