T-ALL Proliferation Relies on Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides
T-ALL Proliferation Relies on Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides
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T-ALL 增殖依赖于谷氨酰胺摄取和 EAAT1 依赖性谷氨酰胺转化为天冬氨酸和核苷酸
DOI：
10.1101/2020.02.08.939694
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Stanulovic V
中科院分区：
文献类型：
--
作者：
Stanulovic V
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 anin silicoscreen and identified a novel EAAT1-specific allosteric inhibitor.
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DOI：
10.1056/nejmoa0900386
发表时间：
2009-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Pui CH;Campana D;Pei D;Bowman WP;Sandlund JT;Kaste SC;Ribeiro RC;Rubnitz JE;Raimondi SC;Onciu M;Coustan-Smith E;Kun LE;Jeha S;Cheng C;Howard SC;Simmons V;Bayles A;Metzger ML;Boyett JM;Leung W;Handgretinger R;Downing JR;Evans WE;Relling MV
通讯作者：
Relling MV
影响因子：
6.5
作者：
Chessells, JM;Veys, P;Hann, IM
通讯作者：
Hann, IM
影响因子：
18.4
作者：
Nagarajan, Arvindhan;Malvi, Parmanand;Wajapeyee, Narendra
通讯作者：
Wajapeyee, Narendra
影响因子：
14.9
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.
影响因子：
5
作者：
Ralphe, JC;Segar, JL;Scholz, TD
通讯作者：
Scholz, TD