Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 34, pages 3593–3604 (2015)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Gokbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Huttmann A et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 2012; 120: 2032–2041.

    Article  Google Scholar 

  2. Van Vlierberghe P, Pieters R, Beverloo HB, Meijerink JP . Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol 2008; 143: 153–168.

    Article  CAS  Google Scholar 

  3. Homminga I, Pieters R, Langerak AW, de Rooi JJ, Stubbs A, Verstegen M et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell 2011; 19: 484–497.

    Article  CAS  Google Scholar 

  4. Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.

    Article  CAS  Google Scholar 

  5. Aster JC, Pear WS, Blacklow SC . Notch Signaling in Leukemia. Annu Rev Pathol 2008; 3: 587–613.

    Article  CAS  Google Scholar 

  6. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 2012; 18: 298–301.

    Article  CAS  Google Scholar 

  7. Chiang MY, Xu L, Shestova O, Histen G, L’heureux S, Romany C et al. Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras–initiated leukemia. J Clin Invest 2008; 118: 3181–3194.

    Article  CAS  Google Scholar 

  8. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ . Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 2007; 110: 278–286.

    Article  CAS  Google Scholar 

  9. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008; 118: 3762–3774.

    Article  CAS  Google Scholar 

  10. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13: 1203–1210.

    Article  CAS  Google Scholar 

  11. Clappier E, Gerby B, Sigaux F, Delord M, Touzri F, Hernandez L et al. Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse. J Exp Med 2011; 208: 653–661.

    Article  CAS  Google Scholar 

  12. Wei G, Twomey D, Lamb J, Schlis K, Agarwal J, Stam RW et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 2006; 10: 331–342.

    Article  CAS  Google Scholar 

  13. Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 2013; 24: 766–776.

    Article  CAS  Google Scholar 

  14. Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell 2014; 25: 366–378.

    Article  CAS  Google Scholar 

  15. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: 647–650.

    Article  CAS  Google Scholar 

  16. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 2013; 31: 4333–4342.

    Article  CAS  Google Scholar 

  17. Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F et al. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med 2011; 208: 1595–1603.

    Article  CAS  Google Scholar 

  18. Bonnet M, Loosveld M, Montpellier B, Navarro JM, Quilichini B, Picard C et al. Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia. Blood 2011; 117: 6650–6659.

    Article  CAS  Google Scholar 

  19. Subramaniam PS, Whye DW, Efimenko E, Chen J, Tosello V, De Keersmaecker K et al. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell 2012; 21: 459–472.

    Article  CAS  Google Scholar 

  20. Curry NL, Mino-Kenudson M, Oliver TG, Yilmaz OH, Yilmaz VO, Moon JY et al. Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction. Cancer Discov 2013; 3: 908–921.

    Article  CAS  Google Scholar 

  21. Ren M, Li X, Cowell JK . Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198-fibroblast growth factor receptor-1 chimeric tyrosine kinase. Blood 2009; 114: 1576–1584.

    Article  CAS  Google Scholar 

  22. Wasag B, Lierman E, Meeus P, Cools J, Vandenberghe P . The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11). Haematologica 2011; 96: 922–926.

    Article  CAS  Google Scholar 

  23. Li Z, Beutel G, Rhein M, Meyer J, Koenecke C, Neumann T et al. High-affinity neurotrophin receptors and ligands promote leukemogenesis. Blood 2009; 113: 2028–2037.

    Article  CAS  Google Scholar 

  24. Segal RA . Selectivity in neurotrophin signaling: theme and variations. Annu Rev Neurosci 2003; 26: 299–330.

    Article  CAS  Google Scholar 

  25. Mulloy JC, Jankovic V, Wunderlich M, Delwel R, Cammenga J, Krejci O et al. AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. Proc Natl Acad Sci USA 2005; 102: 4016–4021.

    Article  CAS  Google Scholar 

  26. Pearse RN . A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood 2005; 105: 4429–4436.

    Article  CAS  Google Scholar 

  27. Renné C, Minner S, Küppers R, Hansmann M-L, Bräuninger A . Autocrine NGFbeta/TRKA signalling is an important survival factor for Hodgkin lymphoma derived cell lines. Leuk Res 2008; 32: 163–167.

    Article  Google Scholar 

  28. Graeber TG, Eisenberg D . Eisenberg_Bioinformatic identification of autocrine loops. Nat Genet 2001; 29: 295–300.

    Article  CAS  Google Scholar 

  29. Meyer J, Rhein M, Schiedlmeier B, Kustikova O, Rudolph C, Kamino K et al. Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, ΔTrkA. Leukemia 2007; 21: 2171–2180.

    Article  CAS  Google Scholar 

  30. Soulier J . HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood 2005; 106: 274–286.

    Article  CAS  Google Scholar 

  31. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y et al. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 1999; 99: 323–334.

    Article  CAS  Google Scholar 

  32. Ashworth TD, Pear WS, Chiang MY, Blacklow SC, Mastio J, Xu L et al. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 2010; 116: 5455–5464.

    Article  CAS  Google Scholar 

  33. Kleppe M, Mentens N, Tousseyn T, Wlodarska I, Cools J . MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context. Haematologica 2011; 96: 779–783.

    Article  CAS  Google Scholar 

  34. Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB et al. Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 2013; 46: 33–38.

    Article  Google Scholar 

  35. Fellmann C, Hoffmann T, Sridhar V, Hopfgartner B, Muhar M, Roth M et al. An optimized microRNA backbone for effective single-copy RNAi. Cell Rep 2013; 5: 1704–1713.

    Article  CAS  Google Scholar 

  36. Rhein M, Schwarzer A, Yang M, Kaever V, Brugman M, Meyer J et al. Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models. Ann Hematol 2011; 90: 283–292.

    Article  CAS  Google Scholar 

  37. Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007; 128: 257–267.

    Article  CAS  Google Scholar 

  38. Chen L, Aktas BH, Wang Y, He X, Sahoo R, Zhang N et al. Tumor suppression by small molecule inhibitors of translation initiation. Oncotarget 2012; 3: 869–881.

    Article  Google Scholar 

  39. Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 2010; 17: 249–261.

    Article  CAS  Google Scholar 

  40. Schatz JH, Oricchio E, Wolfe AL, Jiang M, Linkov I, Maragulia J et al. Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma. J Exp Med 2011; 208: 1799–1807.

    Article  CAS  Google Scholar 

  41. Tamburini J, Green AS, Bardet V, Chapuis N, Park S, Willems L et al. Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia. Blood 2009; 114: 1618–1627.

    Article  CAS  Google Scholar 

  42. Lin C-J, Nasr Z, Premsrirut PK, Porco J, John A, Hippo Y, Lowe SW et al. Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis. Cell Rep 2012; 1: 325–333.

    Article  CAS  Google Scholar 

  43. De Benedetti A, Graff JR . eIF-4E expression and its role in malignancies and metastases. Oncogene 2004; 23: 3189–3199.

    Article  CAS  Google Scholar 

  44. Ramsay G, Evan GI, Bishop JM . The protein encoded by the human proto-oncogene c-myc. Proc Natl Acad Sci USA 1984; 81: 7742–7746.

    Article  CAS  Google Scholar 

  45. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM . A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012; 486: 109–113.

    Article  Google Scholar 

  46. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485: 55–61.

    Article  CAS  Google Scholar 

  47. Laplante M, Sabatini DM . mTOR signaling in growth control and disease. Cell 2012; 149: 274–293.

    Article  CAS  Google Scholar 

  48. Lee K, Nam KT, Cho SH, Gudapati P, Hwang Y, Park D-S et al. Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med 2012; 209: 713–728.

    Article  CAS  Google Scholar 

  49. Fu Z, Tindall DJ . FOXOs, cancer and regulation of apoptosis. Oncogene 2008; 27: 2312–2319.

    Article  CAS  Google Scholar 

  50. Jo OD, Martin J, Bernath A, Masri J, Lichtenstein A, Gera J . Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling. J Biol Chem 2008; 283: 23274–23287.

    Article  CAS  Google Scholar 

  51. Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 2014; 508: 108–112.

    Article  CAS  Google Scholar 

  52. Dello Sbarba P, Rovida E, Marzi I, Cipolleschi MG . One more stem cell niche: how the sensitivity of chronic myeloid leukemia cells to imatinib mesylate is modulated within a ‘hypoxic’ environment. Hypoxia 2014; 2: 1–10.

    Article  Google Scholar 

  53. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 2013; 12: 329–341.

    Article  CAS  Google Scholar 

  54. Lee JY, Nakada D, Yilmaz ÖH, Tothova Z, Joseph NM, Lim MS et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell 2010; 7: 593–605.

    Article  CAS  Google Scholar 

  55. Larsson O, Sonenberg N, Nadon R . anota: analysis of differential translation in genome-wide studies. Bioinformatics 2011; 27: 1440–1441.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

AS was supported by the Hannover Biomedical Research School (HBRS) and the MD-PhD program ‘Molecular Medicine’. We thank Dr Jan Cools, Center for Human Genetics, KULeuven, Leuven for the MOHITO cell line. We thank Dr Phillip Ivanyi and Professor Anke Franzke, Department of Hematology, MHH for providing human T-ALL cell lines. We thank Rena-Mareike Struss, Institute of Experimental Hematology, Hannover Medical School for help with mouse experiments and Anneke Doerrie, Institute of Biochemistry, for assistance in polysome profiling experiments. We thank Axel Schambach, Institute of Experimental Hematology, for providing pRSF91.IRES.dTomato and pRRL.PPT.SF.IRES.EGFP. WPRE vectors. We thank Thomas Neumann and Maike Stahlhut for performing the microarray experiments. We thank the Cell Sorting Unit of Hannover Medical School for performing sorting experiments and Michael Morgan for proofreading the manuscript. This work was supported by the Deutsche Krebshilfe (grants: 108245 and 109800), the Deutsche José Carreras Leukämie-Stiftung (grant: DJCLS F10/06), the Deutsche Forschungsgemeinschaft (grants: Li 1608/2-1 and SFB738) and the DFG-Cluster of Excellence REBIRTH.

Author information

Authors and Affiliations

  1. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany

    A Schwarzer, M Brugman, J Meyer, Z Li & C Baum

  2. Institute of Biochemistry, Hannover Medical School, Hannover, Germany

    H Holtmann & C Schauerte

  3. Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, Vienna, Austria

    J Zuber

  4. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    D Steinemann & B Schlegelberger

Authors
  1. A Schwarzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Holtmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Brugman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Schauerte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Zuber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Steinemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Schlegelberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Z Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Baum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Schwarzer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwarzer, A., Holtmann, H., Brugman, M. et al. Hyperactivation of mTORC1 and mTORC2 by multiple oncogenic events causes addiction to eIF4E-dependent mRNA translation in T-cell leukemia. Oncogene 34, 3593–3604 (2015). https://doi.org/10.1038/onc.2014.290

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.290

This article is cited by

Search

Advanced search

Quick links