Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

Expert Reviews in Molecular Medicine

Volumn 10, Issue 4, 2008, Pages 1-21

  Drakos, Elias ^a   Rassidakis, George Z ^a,b   Medeiros, L Jeffrey ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF ATHENS   (Greece)

Author keywords

[No Author keywords available]

Indexed keywords

AP 23573; DOXORUBICIN; EVEROLIMUS; GLUCOCORTICOID; IMATINIB; INTERLEUKIN 7; LY 29002; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; RAPAMYCIN; RAPAMYCIN DERIVATIVE; RITUXIMAB; TEMSIROLIMUS; VINCRISTINE;

ACUTE LYMPHOBLASTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; ASTHENIA; CELL CYCLE ARREST; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; CYTOTOXICITY; DOWN REGULATION; DRUG DOSE REDUCTION; DRUG POTENTIATION; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; EDEMA; FOLLICULAR LYMPHOMA; GASTROINTESTINAL SYMPTOM; HODGKIN DISEASE; HUMAN; HYPERLIPIDEMIA; HYPERTENSION; IMMUNOSUPPRESSIVE TREATMENT; KIDNEY TRANSPLANTATION; LARGE CELL LYMPHOMA; LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MANTLE CELL LYMPHOMA; MONOTHERAPY; MUCOSA INFLAMMATION; MULTIPLE MYELOMA; NONHODGKIN LYMPHOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN STRUCTURE; SIGNAL TRANSDUCTION; SURVIVAL TIME; THROMBOCYTOPENIA; TRANSLATION REGULATION;

MAMMALIA;

EID: 40349095131     PISSN: 14623994     EISSN: 14623994     Source Type: Journal    
DOI: 10.1017/S1462399408000586     Document Type: Article

References (161)

1. Vezina, 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, 721-726
2. McAlpine, J.B. et al. (1991) Revised NMR assignments for rapamycin. J Antibiot (Tokyo) 44, 688-690
3. Sehgal, S.N. (2003) Sirolimus: Its discovery, biological properties, and mechanism of action. Transplant Proc 35, 7S-14S
4. Douros, J. and Suffness, M. (1981) New antitumor substances of natural origin. Cancer Treat Rev 8, 63-68
5. Faivre, S., Kroemer, G. and Raymond, E. (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5, 671-688
6. Hidalgo, M. (2007) The development of rapamycin as an orphan drug. Clin Adv Hematol Oncol 5, 99-100
7. Harris, T.E. and Lawrence, J.C., Jr, (2003) TOR signaling. Sci STKE, re15
8. Tee, A.R. and Blenis, J. (2005) mTOR, translational control and human disease. Semin Cell Dev Biol 16, 29-37
9. Bjornsti, M.A. and Houghton, P.J. (2004) The TOR pathway: A target for cancer therapy Nat Rev Cancer 4, 335-348
10. Heitman, J., Movva, N.R. and Hall, M.N. (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905-909
11. Kunz, J. et al. (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585-596
12. Helliwell, 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, 105-118
13. Chen, Y. et al. (1994) A putative sirolimus (rapamycin) effector protein. Biochem Biophys Res Commun 203, 1-7
14. Sabatini, 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, 35-43
15. Brown, E.J. et al. (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756-758
16. Sabers, C.J. et al. (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270, 815-822
17. Brunn, G.J. et al. (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99-101
18. Burnett, 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, 1432-1437
19. Cardenas, M.E. and Heitman, J. (1995) FKBP12-rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol-4 kinase activity. Embo J 14, 5892-5907
20. Abraham, R.T. (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15, 2177-2196
21. Andrade, M.A. and Bork, P (1995) HEAT repeats in the Huntington's disease protein. Nat Genet 11, 115-116
22. Bosotti, R., Isacchi, A. and Sonnhammer, E.L. (2000) FAT: A novel domain in PIK-related kinases. Trends Biochem Sci 25, 225-227
23. Peterson, R.T. et al. (2000) FKBP12-raparnycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 275, 7416-7423
24. Takahashi, 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, 765-775
25. Sekulic, 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, 3504-3513
26. Cafferkey, R. et al. (1994) Yeast TOR (DRR) proteins: Amino-acid sequence alignment and identification of structural motifs. Gene 141, 133-136
27. Loewith, R. et al. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10, 457-468
28. Kim, 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, 895-904
29. Hara, K. et al. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action Cell 110, 177-189
30. Kim, D.H. et al. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery Cell 110, 163-175
31. Sarbassov, D.D. et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 30, 1098-1101
32. Sarbassov, D.D., Ali, S.M. and Sabatini, D.M. (2005) Growing roles for the mTOR pathway Curr Opin Cell Biol 17, 596-603
33. Sarbassov, 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, 1296-1302
34. Jacinto, E. et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6, 1122-1128
35. Jacinto, E. et al. (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125-137
36. Frias, M.A. et al. (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16, 1865-1870
37. Ruggero, D. and Pandolfi, P.P. (2003) Does the ribosome translate cancer? Nat Rev Cancer 3, 179-192
38. Beretta, L. et al. (1996) Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. Embo J 15, 658-664
39. Price, D.J. et al. (1992) Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 257, 973-977
40. Chung, J. et al. (1992) Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227-1236
41. Hay, N. and Sonenberg, N. (2004) Upstream and downstream of mTOR. Genes Dev 18, 1926-1945
42. Gingras, 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, 913-963
43. Gingras, A.C., Raught, B. and Sonenberg, N. (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev, 15: 807-826
44. Wang, X. and Proud, C.G. (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21, 362-369
45. Meyuhas, O. (2000) Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem 267, 6321-6330
46. Pende, 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. Mot Cell Biol 24, 3112-3124
47. Tang, 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, 8671-8683
48. Stolovich, 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, 8101-8113
49. Peterson, T.R. and Sabatini, D.M. (2005) eIF3: A connecTOR of S6K1 to the translation preinitiation complex. Mol Cell 20, 655-657
50. Holz, 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, 569-580
51. Shahbazian, D. et al. (2006) The mTOR/Pl3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. Embo J 25, 2781-2791
52. Browne, G.J. and Proud, C.G. (2002) Regulation of peptide-chain elongation in mammalian cells. Eur J Biochem 269, 5360-5368
53. Wang, X. et al. (2001) Regulation of elongation factor 2 kinase by pp90(RSK1) and p70 S6 kinase. Embo J 20, 4370-4379
54. Mayer, C. and Grummt, I. (2006) Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25, 6384-6391
55. Mayer, C. et al. (2004) mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18, 423-434
56. Hannan, 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, 8862-8877
57. Shintani, T. and Klionsky, D.J. (2004) Autophagy in health and disease: a double-edged sword. Science 306, 990-995
58. Kamada, Y. et al. (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150, 1507-1513
59. Mordier, 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, 29900-29906
60. Tapon, N. et al. (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345-355
61. Gao, X. et al. (2002) Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4, 699-704
62. Goncharova, E.A. et al. (2002) Tuberin regulates p7O S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 277, 30958-30967
63. Kwiatkowski, 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, 525-534
64. Saucedo, L.J. et al. (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5, 566-571
65. Stocker, H. et al. (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5, 559-565
66. Zhang, Y. et al. (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5, 578-581
67. Tee, 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, 1259-1268
68. Long, X. et al. (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15, 702-713
69. Cantley, L.C. (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655-1657
70. Johnson, G.L. and Lapadat, R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911-1912
71. Roux, 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, 320-344
72. Inoki, K. et al. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4, 648-657
73. Potter, C.J., Pedraza, L.G. and Xu, T. (2002) Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4, 658-665
74. Ma, L. et al. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179-193
75. Ballif, 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, 667-672
76. Roux, 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, 13489-13494
77. Wullschleger, S., Loewith, R. and Hall, M.N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484
78. Inoki, K., Zhu, T. and Guan, K.L. (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590
79. Corradetti, 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, 1533-1538
80. Shaw, R.J. et al. (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91-99
81. Feng, Z. et al. (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102, 8204-8209
82. Byfield, 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, 33076-33082
83. Nobukuni, T. et al. (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 30H-kinase. Proc Natl Acad Sci U S A 102, 14238-14243
84. Reiling, J.H. and Sabatini, D.M. (2006) Stress and mTORture signaling. Oncogene 25, 6373-6383
85. Brugarolas, J. et al. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18, 2893-2904
86. Reiling, 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, 2879-2892
87. Shaw, R.J. and Cantley, L.C. (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424-430
88. Cully, M. et al. (2006) Beyond PTEN mutations: The PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6, 184-192
89. Liang, X.H. et al. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672-676
90. Yue, 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, 15077-15082
91. Averous, J. and Proud, C.G. (2006) When translation meets transformation: The mTOR story Oncogene 25, 6423-6435
92. Ruggero, D. et al. (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10, 484-486
93. Wendel, H.G. et al. (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy Nature 428, 332-337
94. Jaffe, E. et al. (Eds) (2001) Pathology and genetics of tumors of hematopoietic and lymphoid tissues. World Health Organization Classification of Tumours. IARC Press, Lyon
95. Montagne, J. et al. (1999) Drosophila S6 kinase: A regulator of cell size. Science 285, 2126-2129
96. Stocker, H. and Hafen, E. (2000) Genetic control of cell size. Curr Opin Genet Dev 10, 529-535
97. Fingar, D.C. et al. (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16, 1472-1487
98. Isaacson, T.V. et al. (2007) Expression of mTOR pathway proteins in malignant lymphoma. Lab Invest 87, 246A
99. Jundt, 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, 1801-1807
100. Georgakis, 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, 503-511
101. Dutton, 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, 498-506
102. Zheng, 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, 1019-1027
103. Watanabe, 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, 7628-7634
104. Vega, 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, 6589-6597
105. Marzec, M. et al. (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene 38, 5606-5614
106. Rassidakis, G.Z. et al. (2005) Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105, 827-829
107. Bai, 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, 4319-4327
108. Marzec, M. et al. (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. Oncogene 26, 813-821
109. Gu, 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, 4622-4629
110. Pulford, K., Morris, S.W. and Turturro, F. (2004) Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 199, 330-358
111. Peponi, 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, 2171-2180
112. Hipp, 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, 1433-1434
113. Haritunians, T. et al. (2007) Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2, 333-339
114. Rudelius, M. et al. (2006) Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 108, 1668-1676
115. Decker, 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, 558-568
116. Decker, 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, 327-334
117. Decker, 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, 278-285
118. Zanesi, 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, 915-920
119. Bichi, R. et al. (2002) Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci U S A 99, 6955-6960
120. Brown, 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, 15113-15118
121. Iwamoto, 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, 1809-1814
122. Wasserman, R., Zeng, X.X. and Hardy, R.R. (1998) The evolution of B precursor leukemia in the Emuret mouse. Blood 92, 273-282
123. Zeng, X.X. et al. (1998) The fetal origin of B-precursor leukemia in the E-mu-ret mouse. Blood 92, 3529-3536
124. Teachey, D.T. et al. (2006) Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood 108, 1965-1971
125. Prabhu, 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, 1188-1200
126. Burchert, A. et al. (2005) Compensatory P13-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19, 1774-1782
127. Avellino, R. et al. (2005) Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106, 1400-1406
128. Wei, G. et al. (2006) Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10, 331-342
129. Mungamuri, S.K. et al. (2006) Survival signaling by Notch1: Mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 66, 4715-4724
130. Warmer, 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, 475-484
131. Uddin, S. et al. (2006) Role of phosphatidylinositol 3Pm-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood 108, 4178-4186
132. Sin, S.H. et al. (2007) Ra amycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 109, 2165-2173
133. Uddin, S. et al. (2005) Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin Cancer Res 11, 3102-3108
134. Leseux, L. et al. (2006) Syk-dependent mTOR activation in follicular lymphoma cells. Blood 108, 4156-4162
135. Calastretti, A. et al. (2001) Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase. Oncogene 20, 6172-6180
136. Ogata, A. et al. (1997) IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 159, 2212-2221
137. Hsu, J. et al. (2001) The AKT kinase is activated in multiple myeloma tumor cells. Blood 98, 2853-2855
138. Pene, E et al. (2002) Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P7OS6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 21, 6587-6597
139. Hu, L. et al. (2003) Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 101, 3126-3135
140. Frost, 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, 4181-4187
141. Shi Y. et al. (2002) Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62, 5027-5034
142. Stromberg, T. et al. (2004) Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103, 3138-3147
143. Yarj, H. et al. (2006) Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res 66, 2305-2313
144. Baylink, D.J., Finkelman, R.D. and Mohan, S. (1993) Growth factors to stimulate bone formation. J Bone Miner Res 8 Suppl 2, S565-572
145. Frost, P. et al. (2007) AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene 26, 2255-2262
146. Majewski, 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, 1710-1717
147. Majewski, 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, 4285-4290
148. Nepomuceno, 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, 4472-4480
149. Wlodarski, 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, 7800-7808
150. Dancey, J.E. (2005) Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs 14, 313-328
151. Murakami, M. et al. (2004) mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 24, 6710-6718
152. Gangloff, YG. et al. (2004) Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 24, 9508-9516
153. Sarbassov, D.D. et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22, 159-168
154. Witzig, TE. and Kaufmann, S.H. (2006) Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 7, 285-294
155. Costa, L.J. (2007) Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin's lymphoma. Cancer Treat Rev 33, 78-84
156. Witzig, T.E. et al. (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23, 5347-5356
157. Yee, 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, 5165-5173
158. Shi, 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, 1533-1540
159. Sun, S.Y. et al. (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65, 7052-7058
160. Zeng, Z. et al. (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509-3512
161. Guertin, D.A. and Sabatini, D.M. (2007) Defining the role of mTOR in cancer. Cancer Cell 12, 9-22