title: Hyperactivation of mTORC1 and mTORC2 by multiple oncogenic events causes addiction to eIF4E-dependent mRNA translation in T-cell leukemia.
abstract: 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.
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schwarzer
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Holtmann
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Brugman
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Meyer
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schauerte
authors.affiliation: Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Steinemann
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Baum
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases