Hyperactivation of mTORC1 and mTORC2 by multiple oncogenic events causes addiction to eIF4E-dependent mRNA translation in T-cell leukemia

• Published in: Oncogene 2015-07, Vol.34 (27), p.3593-3604
• Main Authors: Schwarzer, A, Holtmann, H, Brugman, M, Meyer, J, Schauerte, C, Zuber, J, Steinemann, D, Schlegelberger, B, Li, Z, Baum, C
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/31; 13/44; 13/89; 13/95; 38/61; 38/90; 45/23; 631/67/1990/283/2125; 64/60; 96/1; Acute lymphoblastic leukemia; Addictions; AKT protein; Animal models; Animals; Apoptosis; Cell activation; Cell Biology; Cell cycle; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells; Cellular proteins; Cellular signal transduction; Cyclins; Cytotoxicity; Development and progression; Drug resistance; Drug therapy; Eukaryotic Initiation Factor-4E - physiology; Gene Expression Regulation, Leukemic; Genetic aspects; Genomes; Health aspects; Homeobox; Human Genetics; Humans; Initiation factor eIF-4E; Initiation factor eIF-4G; Internal Medicine; Leukemia; Leukemia, T-Cell - genetics; Leukemia, T-Cell - metabolism; Lymphatic leukemia; Lymphocytes T; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Medicine; Medicine & Public Health; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Multiprotein Complexes - metabolism; Notch1 protein; Oncology; original-article; Properties; Protein Biosynthesis - genetics; Protein-tyrosine kinase receptors; PTEN protein; Ribonucleic acid; Ribosomal proteins; RNA; Signal Transduction; Thymocytes; TOR Serine-Threonine Kinases - metabolism; Tumor Cells, Cultured
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.290

High activation of the PI3K–AKT–mTOR pathway is characteristic for T-cell acute lymphoblastic leukemia (T-ALL). The activity of the master regulator of this pathway, PTEN, is often impaired in T-ALL. However, experimental evidence suggests that input from receptor tyrosine kinases (RTKs) is required for sustained mTOR activation, even in the absence of PTEN. We previously reported the expression of Neurotrophin receptor tyrosine kinases (TRKs) and their respective ligands in primary human leukemia samples. In the present study we aimed to dissect the downstream signaling cascades of TRK-induced T-ALL in a murine model and show that T-ALLs induced by deregulated receptor tyrosine kinase signaling acquire activating mutations in Notch1 and lose PTEN during clonal evolution. Some clones additionally lost one allele of the homeodomain transcription factor Cux1. All events independently led to a gradual hyperactivation of both mTORC1 and mTORC2 signaling. We dissected the role of the individual mTOR complexes by shRNA knockdown and found that the separate depletion of mTORC1 or mTORC2 reduced the growth of T-ALL blasts, but was not sufficient to induce apoptosis. In contrast, knockdown of the mTOR downstream effector eIF4E caused a striking cytotoxic effect, demonstrating a critical addiction to cap-dependent mRNA-translation. Although high mTORC2–AKT activation is commonly associated with drug-resistance, we demonstrate that T-ALL displaying a strong mTORC2–AKT activation were specifically susceptible to 4EGI-1, an inhibitor of the eIF4E–eIF4G interaction. To decipher the mechanism of 4EGI-1, we performed a genome-wide analysis of mRNAs that are translationally regulated by 4EGI-1 in T-ALL. 4EGI-1 effectively reduced the ribosomal occupancy of mRNAs that were strongly upregulated in T-ALL blasts compared with normal thymocytes including transcripts important for translation, mitochondria and cell cycle progression, such as cyclins and ribosomal proteins. These data suggest that disrupting the eIF4E–eIF4G interaction constitutes a promising therapy strategy in mTOR-deregulated T-cell leukemia.