Control of amino-acid transport coordinates metabolic reprogramming in T cell malignancy

Analysis of murine model of T cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) reveals that primary T-ALL cells have high transport rates for multiple nutrients. In particular, high levels of leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1a (HIF1a) and c-Myc, the drivers of glucose transport. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1a or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the dominant System L-amino acid transporter in primary PTEN-/- T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data highlight the importance of regulated amino acid transport for T cell malignancies and how a single amino acid transporter can play a key role.