Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham.
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham.
Haematologica. 2024 Nov 1;109(11):3505-3519. doi: 10.3324/haematol.2023.283471.
T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of pediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the tricarboxylic acid cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.
T 细胞急性淋巴细胞白血病（T-ALL）是一种免疫系统癌症。大约 20%的儿科和 50%的成人 T-ALL 患者患有难治性疾病或复发，并因此病而死亡。为了改善患者的预后，需要新的治疗方法。为了寻找新的治疗靶点，我们结合 T-ALL 基因表达和代谢的分析，确定了 T-ALL 细胞表现出的代谢适应。我们发现，谷氨酰胺摄取对于 T-ALL 的增殖是必不可少的。同位素示踪实验表明，谷氨酰胺通过三羧酸循环为天冬氨酸合成提供燃料，而谷氨酰胺和谷氨酰胺衍生的天冬氨酸一起为嘌呤中的三个氮原子和嘧啶环中的除一个原子提供氮原子。我们表明，通常在中枢神经系统中表达的谷氨酸-天冬氨酸转运体 EAAT1（SLC1A3）对于谷氨酰胺转化为天冬氨酸和核苷酸至关重要，并且 T-ALL 细胞的增殖依赖于 EAAT1 的功能。通过这项工作，我们确定 EAAT1 是治疗 T-ALL 的一个新的治疗靶点。
