Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-03T02:54:29.311Z Has data issue: false hasContentIssue false
  • English
  • Français

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

Published online by Cambridge University Press:  04 February 2008

Elias Drakos ,
George Z. Rassidakis  and
L. Jeffrey Medeiros
Elias Drakos
Affiliation:
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
George Z. Rassidakis
Affiliation:
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. First Department of Pathology, National and Kapodistrian University of Athens, Athens, Greece.
L. Jeffrey Medeiros*
Affiliation:
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
*
*Corresponding author: L. Jeffrey Medeiros, Department of Hematopathology, Unit 72, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Tel: +1 713 794 5446; Fax: +1 713 745 0736; Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

The mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e4
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Vezina, C., Kudelski, A. and Sehgal, S.N. (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28, 721-726CrossRefGoogle ScholarPubMed
2McAlpine, J.B. et al. (1991) Revised NMR assignments for rapamycin. J Antibiot (Tokyo) 44, 688-690CrossRefGoogle ScholarPubMed
3Sehgal, S.N. (2003) Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35, 7S-14SCrossRefGoogle ScholarPubMed
4Douros, J. and Suffness, M. (1981) New antitumor substances of natural origin. Cancer Treat Rev 8, 63-68CrossRefGoogle ScholarPubMed
5Faivre, S., Kroemer, G. and Raymond, E. (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5, 671-688CrossRefGoogle ScholarPubMed
6Hidalgo, M. (2007) The development of rapamycin as an orphan drug. Clin Adv Hematol Oncol 5, 99-100Google ScholarPubMed
7Harris, T.E. and Lawrence, J.C. Jr, (2003) TOR signaling. Sci STKE, re15CrossRefGoogle ScholarPubMed
8Tee, A.R. and Blenis, J. (2005) mTOR, translational control and human disease. Semin Cell Dev Biol 16, 29-37CrossRefGoogle ScholarPubMed
9Bjornsti, M.A. and Houghton, P.J. (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4, 335-348CrossRefGoogle ScholarPubMed
10Heitman, J., Movva, N.R. and Hall, M.N. (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905-909CrossRefGoogle ScholarPubMed
11Kunz, J. et al. (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585-596CrossRefGoogle ScholarPubMed
12Helliwell, S.B. et al. (1994) TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell 5, 105-118CrossRefGoogle Scholar
13Chen, Y. et al. (1994) A putative sirolimus (rapamycin) effector protein. Biochem Biophys Res Commun 203, 1-7CrossRefGoogle ScholarPubMed
14Sabatini, D.M. et al. (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35-43CrossRefGoogle Scholar
15Brown, E.J. et al. (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756-758CrossRefGoogle ScholarPubMed
16Sabers, C.J. et al. (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270, 815-822CrossRefGoogle ScholarPubMed
17Brunn, G.J. et al. (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99-101CrossRefGoogle ScholarPubMed
18Burnett, P.E. et al. (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A 95, 1432-1437CrossRefGoogle ScholarPubMed
19Cardenas, M.E. and Heitman, J. (1995) FKBP12-rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol-4 kinase activity. Embo J 14, 5892-5907CrossRefGoogle ScholarPubMed
20Abraham, R.T. (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15, 2177-2196CrossRefGoogle ScholarPubMed
21Andrade, M.A. and Bork, P. (1995) HEAT repeats in the Huntington's disease protein. Nat Genet 11, 115-116CrossRefGoogle ScholarPubMed
22Bosotti, R., Isacchi, A. and Sonnhammer, E.L. (2000) FAT: a novel domain in PIK-related kinases. Trends Biochem Sci 25, 225-227CrossRefGoogle ScholarPubMed
23Peterson, R.T. et al. (2000) FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 275, 7416-7423CrossRefGoogle ScholarPubMed
24Takahashi, T. et al. (2000) Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro. Genes Cells 5, 765-775CrossRefGoogle ScholarPubMed
25Sekulic, A. et al. (2000) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60, 3504-3513Google ScholarPubMed
26Cafferkey, R. et al. (1994) Yeast TOR (DRR) proteins: amino-acid sequence alignment and identification of structural motifs. Gene 141, 133-136CrossRefGoogle ScholarPubMed
27Loewith, R. et al. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10, 457-468CrossRefGoogle ScholarPubMed
28Kim, D.H. et al. (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11, 895-904CrossRefGoogle ScholarPubMed
29Hara, K. et al. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189CrossRefGoogle ScholarPubMed
30Kim, D.H. et al. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175CrossRefGoogle Scholar
31Sarbassov, D.D. et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 30, 1098-1101CrossRefGoogle Scholar
32Sarbassov, D.D., Ali, S.M. and Sabatini, D.M. (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17, 596-603CrossRefGoogle ScholarPubMed
33Sarbassov, D.D. et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14, 1296-1302CrossRefGoogle ScholarPubMed
34Jacinto, E. et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6, 1122-1128CrossRefGoogle ScholarPubMed
35Jacinto, E. et al. (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125-137CrossRefGoogle ScholarPubMed
36Frias, M.A. et al. (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16, 1865-1870CrossRefGoogle ScholarPubMed
37Ruggero, D. and Pandolfi, P.P. (2003) Does the ribosome translate cancer? Nat Rev Cancer 3, 179-192CrossRefGoogle ScholarPubMed
38Beretta, L. et al. (1996) Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. Embo J 15, 658-664CrossRefGoogle ScholarPubMed
39Price, D.J. et al. (1992) Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 257, 973-977CrossRefGoogle ScholarPubMed
40Chung, J. et al. (1992) Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227-1236CrossRefGoogle ScholarPubMed
41Hay, N. and Sonenberg, N. (2004) Upstream and downstream of mTOR. Genes Dev 18, 1926-1945CrossRefGoogle ScholarPubMed
42Gingras, A.C., Raught, B. and Sonenberg, N. (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68, 913-963CrossRefGoogle ScholarPubMed
43Gingras, A.C., Raught, B. and Sonenberg, N. (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev, 15: 807-826CrossRefGoogle ScholarPubMed
44Wang, X. and Proud, C.G. (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21, 362-369Google ScholarPubMed
45Meyuhas, O. (2000) Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem 267, 6321-6330CrossRefGoogle ScholarPubMed
46Pende, M. et al. (2004) S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24, 3112-3124CrossRefGoogle Scholar
47Tang, H. et al. (2001) Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol Cell Biol 21, 8671-8683CrossRefGoogle ScholarPubMed
48Stolovich, M. et al. (2002) Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol Cell Biol 22, 8101-8113CrossRefGoogle ScholarPubMed
49Peterson, T.R. and Sabatini, D.M. (2005) eIF3: a connecTOR of S6K1 to the translation preinitiation complex. Mol Cell 20, 655-657CrossRefGoogle Scholar
50Holz, M.K. et al. (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569-580CrossRefGoogle ScholarPubMed
51Shahbazian, D. et al. (2006) The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. Embo J 25, 2781-2791CrossRefGoogle ScholarPubMed
52Browne, G.J. and Proud, C.G. (2002) Regulation of peptide-chain elongation in mammalian cells. Eur J Biochem 269, 5360-5368CrossRefGoogle ScholarPubMed
53Wang, X. et al. (2001) Regulation of elongation factor 2 kinase by pp90(RSK1) and p70 S6 kinase. Embo J 20, 4370-4379CrossRefGoogle Scholar
54Mayer, C. and Grummt, I. (2006) Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25, 6384-6391CrossRefGoogle ScholarPubMed
55Mayer, C. et al. (2004) mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18, 423-434CrossRefGoogle ScholarPubMed
56Hannan, K.M. et al. (2003) mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol 23, 8862-8877CrossRefGoogle ScholarPubMed
57Shintani, T. and Klionsky, D.J. (2004) Autophagy in health and disease: a double-edged sword. Science 306, 990-995CrossRefGoogle ScholarPubMed
58Kamada, Y. et al. (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150, 1507-1513CrossRefGoogle ScholarPubMed
59Mordier, S. et al. (2000) Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway. J Biol Chem 275, 29900-29906CrossRefGoogle ScholarPubMed
60Tapon, N. et al. (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345-355CrossRefGoogle ScholarPubMed
61Gao, X. et al. (2002) Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4, 699-704CrossRefGoogle ScholarPubMed
62Goncharova, E.A. et al. (2002) Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 277, 30958-30967CrossRefGoogle ScholarPubMed
63Kwiatkowski, D.J. et al. (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70 S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11, 525-534CrossRefGoogle Scholar
64Saucedo, L.J. et al. (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5, 566-571CrossRefGoogle ScholarPubMed
65Stocker, H. et al. (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5, 559-565CrossRefGoogle ScholarPubMed
66Zhang, Y. et al. (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5, 578-581CrossRefGoogle ScholarPubMed
67Tee, A.R. et al. (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13, 1259-1268CrossRefGoogle ScholarPubMed
68Long, X. et al. (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15, 702-713CrossRefGoogle ScholarPubMed
69Cantley, L.C. (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655-1657CrossRefGoogle ScholarPubMed
70Johnson, G.L. and Lapadat, R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911-1912CrossRefGoogle ScholarPubMed
71Roux, P.P. and Blenis, J. (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68, 320-344CrossRefGoogle ScholarPubMed
72Inoki, K. et al. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4, 648-657CrossRefGoogle ScholarPubMed
73Potter, C.J., Pedraza, L.G. and Xu, T. (2002) Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4, 658-665CrossRefGoogle ScholarPubMed
74Ma, L. et al. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179-193CrossRefGoogle ScholarPubMed
75Ballif, B.A. et al. (2005) Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc Natl Acad Sci U S A 102, 667-672CrossRefGoogle ScholarPubMed
76Roux, P.P. et al. (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A 101, 13489-13494CrossRefGoogle ScholarPubMed
77Wullschleger, S., Loewith, R. and Hall, M.N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484CrossRefGoogle ScholarPubMed
78Inoki, K., Zhu, T. and Guan, K.L. (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590CrossRefGoogle ScholarPubMed
79Corradetti, M.N. et al. (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18, 1533-1538CrossRefGoogle ScholarPubMed
80Shaw, R.J. et al. (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91-99CrossRefGoogle ScholarPubMed
81Feng, Z. et al. (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102, 8204-8209CrossRefGoogle ScholarPubMed
82Byfield, M.P., Murray, J.T. and Backer, J.M. (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280, 33076-33082CrossRefGoogle ScholarPubMed
83Nobukuni, T. et al. (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A 102, 14238-14243CrossRefGoogle ScholarPubMed
84Reiling, J.H. and Sabatini, D.M. (2006) Stress and mTORture signaling. Oncogene 25, 6373-6383CrossRefGoogle ScholarPubMed
85Brugarolas, J. et al. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18, 2893-2904CrossRefGoogle ScholarPubMed
86Reiling, J.H. and Hafen, E. (2004) The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18, 2879-2892CrossRefGoogle ScholarPubMed
87Shaw, R.J. and Cantley, L.C. (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424-430CrossRefGoogle ScholarPubMed
88Cully, M. et al. (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6, 184-192CrossRefGoogle ScholarPubMed
89Liang, X.H. et al. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672-676CrossRefGoogle ScholarPubMed
90Yue, Z. et al. (2001) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100, 15077-15082CrossRefGoogle Scholar
91Averous, J. and Proud, C.G. (2006) When translation meets transformation: the mTOR story. Oncogene 25, 6423-6435CrossRefGoogle ScholarPubMed
92Ruggero, D. et al. (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10, 484-486CrossRefGoogle ScholarPubMed
93Wendel, H.G. et al. (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332-337CrossRefGoogle ScholarPubMed
94Jaffe, E. et al. (Eds) (2001) Pathology and genetics of tumors of hematopoietic and lymphoid tissues. World Health Organization Classification of Tumours. IARC Press, LyonGoogle Scholar
95Montagne, J. et al. (1999) Drosophila S6 kinase: a regulator of cell size. Science 285, 2126-2129CrossRefGoogle ScholarPubMed
96Stocker, H. and Hafen, E. (2000) Genetic control of cell size. Curr Opin Genet Dev 10, 529-535CrossRefGoogle ScholarPubMed
97Fingar, D.C. et al. (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16, 1472-1487CrossRefGoogle ScholarPubMed
98Isaacson, T.V. et al. (2007) Expression of mTOR pathway proteins in malignant lymphoma. Lab Invest 87, 246AGoogle Scholar
99Jundt, F. et al. (2005) A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein {beta} and NF-{kappa}B activity in Hodgkin and anaplastic large cell lymphomas. Blood 106, 1801-1807CrossRefGoogle ScholarPubMed
100Georgakis, G.V. et al. (2006) Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol 132, 503-511CrossRefGoogle ScholarPubMed
101Dutton, A. et al. (2005) Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol 205, 498-506CrossRefGoogle Scholar
102Zheng, B. et al. (2003) MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood 102, 1019-1027CrossRefGoogle ScholarPubMed
103Watanabe, M. et al. (2005) JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and reed-sternberg cells of Hodgkin lymphoma. Cancer Res 65, 7628-7634CrossRefGoogle ScholarPubMed
104Vega, F. et al. (2006) Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res 66, 6589-6597CrossRefGoogle ScholarPubMed
105Marzec, M. et al. (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene 38, 5606-5614CrossRefGoogle Scholar
106Rassidakis, G.Z. et al. (2005) Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105, 827-829CrossRefGoogle ScholarPubMed
107Bai, R.Y. et al. (2000) Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96, 4319-4327CrossRefGoogle ScholarPubMed
108Marzec, M. et al. (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. Oncogene 26, 813-821CrossRefGoogle ScholarPubMed
109Gu, T.L. et al. (2004) NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a. Blood 103, 4622-4629CrossRefGoogle ScholarPubMed
110Pulford, K., Morris, S.W. and Turturro, F. (2004) Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 199, 330-358CrossRefGoogle ScholarPubMed
111Peponi, E. et al. (2006) Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. Am J Pathol 169, 2171-2180CrossRefGoogle ScholarPubMed
112Hipp, S. et al. (2005) Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica 90, 1433-1434Google ScholarPubMed
113Haritunians, T. et al. (2007) Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2, 333-339CrossRefGoogle Scholar
114Rudelius, M. et al. (2006) Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 108, 1668-1676CrossRefGoogle Scholar
115Decker, T. et al. (2000) Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp Hematol 28, 558-568CrossRefGoogle Scholar
116Decker, T. et al. (2002) Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor 27. Leukemia 16, 327-334CrossRefGoogle Scholar
117Decker, T. et al. (2003) Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood 101, 278-285CrossRefGoogle ScholarPubMed
118Zanesi, N. et al. (2006) Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice. Cancer Res 66, 915-920CrossRefGoogle ScholarPubMed
119Bichi, R. et al. (2002) Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci U S A 99, 6955-6960CrossRefGoogle ScholarPubMed
120Brown, V.I. et al. (2003) Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A 100, 15113-15118CrossRefGoogle ScholarPubMed
121Iwamoto, T. et al. (1991) Preferential development of pre-B lymphomas with drastically down-regulated N-myc in the E mu-ret transgenic mice. Eur J Immunol 21, 1809-1814CrossRefGoogle ScholarPubMed
122Wasserman, R., Zeng, X.X. and Hardy, R.R. (1998) The evolution of B precursor leukemia in the Emu-ret mouse. Blood 92, 273-282CrossRefGoogle ScholarPubMed
123Zeng, X.X. et al. (1998) The fetal origin of B-precursor leukemia in the E-mu-ret mouse. Blood 92, 3529-3536CrossRefGoogle ScholarPubMed
124Teachey, D.T. et al. (2006) Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood 108, 1965-1971CrossRefGoogle ScholarPubMed
125Prabhu, S. et al. (2007) Novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene 26, 1188-1200CrossRefGoogle ScholarPubMed
126Burchert, A. et al. (2005) Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19, 1774-1782CrossRefGoogle ScholarPubMed
127Avellino, R. et al. (2005) Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106, 1400-1406CrossRefGoogle ScholarPubMed
128Wei, G. et al. (2006) Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10, 331-342CrossRefGoogle ScholarPubMed
129Mungamuri, S.K. et al. (2006) Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 66, 4715-4724CrossRefGoogle ScholarPubMed
130Wanner, K. et al. (2006) Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 134, 475-484CrossRefGoogle ScholarPubMed
131Uddin, S. et al. (2006) Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood 108, 4178-4186CrossRefGoogle ScholarPubMed
132Sin, S.H. et al. (2007) Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 109, 2165-2173CrossRefGoogle ScholarPubMed
133Uddin, S. et al. (2005) Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin Cancer Res 11, 3102-3108CrossRefGoogle ScholarPubMed
134Leseux, L. et al. (2006) Syk-dependent mTOR activation in follicular lymphoma cells. Blood 108, 4156-4162CrossRefGoogle ScholarPubMed
135Calastretti, A. et al. (2001) Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase. Oncogene 20, 6172-6180CrossRefGoogle ScholarPubMed
136Ogata, A. et al. (1997) IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 159, 2212-2221CrossRefGoogle ScholarPubMed
137Hsu, J. et al. (2001) The AKT kinase is activated in multiple myeloma tumor cells. Blood 98, 2853-2855CrossRefGoogle ScholarPubMed
138Pene, F. et al. (2002) Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 21, 6587-6597CrossRefGoogle ScholarPubMed
139Hu, L. et al. (2003) Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 101, 3126-3135CrossRefGoogle Scholar
140Frost, P. et al. (2004) In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 104, 4181-4187CrossRefGoogle Scholar
141Shi, Y. et al. (2002) Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62, 5027-5034Google ScholarPubMed
142Stromberg, T. et al. (2004) Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103, 3138-3147CrossRefGoogle ScholarPubMed
143Yan, H. et al. (2006) Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res 66, 2305-2313CrossRefGoogle ScholarPubMed
144Baylink, D.J., Finkelman, R.D. and Mohan, S. (1993) Growth factors to stimulate bone formation. J Bone Miner Res 8 Suppl 2, S565-572CrossRefGoogle Scholar
145Frost, P. et al. (2007) AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene 26, 2255-2262CrossRefGoogle ScholarPubMed
146Majewski, M. et al. (2003) Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 75, 1710-1717CrossRefGoogle ScholarPubMed
147Majewski, M. et al. (2000) The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci U S A 97, 4285-4290CrossRefGoogle ScholarPubMed
148Nepomuceno, R.R. et al. (2003) Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 63, 4472-4480Google ScholarPubMed
149Wlodarski, P. et al. (2005) Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, insulin growth factor-I, and serum. Cancer Res 65, 7800-7808CrossRefGoogle ScholarPubMed
150Dancey, J.E. (2005) Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs 14, 313-328CrossRefGoogle ScholarPubMed
151Murakami, M. et al. (2004) mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 24, 6710-6718CrossRefGoogle ScholarPubMed
152Gangloff, Y.G. et al. (2004) Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 24, 9508-9516CrossRefGoogle ScholarPubMed
153Sarbassov, D.D. et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22, 159-168CrossRefGoogle Scholar
154Witzig, T.E. and Kaufmann, S.H. (2006) Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 7, 285-294CrossRefGoogle ScholarPubMed
155Costa, L.J. (2007) Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin's lymphoma. Cancer Treat Rev 33, 78-84CrossRefGoogle ScholarPubMed
156Witzig, T.E. et al. (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23, 5347-5356CrossRefGoogle ScholarPubMed
157Yee, K.W. et al. (2006) Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12, 5165-5173CrossRefGoogle ScholarPubMed
158Shi, Y. et al. (2005) Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4, 1533-1540CrossRefGoogle ScholarPubMed
159Sun, S.Y. et al. (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65, 7052-7058CrossRefGoogle ScholarPubMed
160Zeng, Z. et al. (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509-3512CrossRefGoogle ScholarPubMed
161Guertin, D.A. and Sabatini, D.M. (2007) Defining the role of mTOR in cancer. Cancer Cell 12, 9-22CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Guertin, D.A. and Sabatini, D.M. (2007) Defining the role of mTOR in cancer. Cancer Cell 12, 9-22CrossRefGoogle ScholarPubMed
Jaffe, E. et al. (eds) (2001) Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours, IARC Press, LyonGoogle Scholar
http://www.cancer.gov/clinicaltrials and http://www.citeline.com.Google Scholar