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A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation

Oncogene volume 26, pages 1188–1200 (2007)Cite this article

Abstract

The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.

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References

  • Altmann M, Schmitz N, Berset C, Trachsel H . (1997). A novel inhibitor of cap-dependent translation initiation in yeast: p20 competes with eIF4G for binding to eIF4E. EMBO J 16: 1114–1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Avdulov S, Li S, Van M, Burrichter D, Peterson M, Perlman DM et al. (2004). Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5: 553–563.

    Article  CAS  PubMed  Google Scholar 

  • Bordeleau ME, Matthews J, Wojnar JM, Lindqvist L, Novac O, Jankowsky E et al. (2005). Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation. Proc Natl Acad Sci USA 102: 10460–10465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bushell M, Poncet D, Marissen WE, Flotow H, Lloyd RE, Clemens MJ et al. (2000). Cleavage of polypeptide chain initiation factor eIF4GI during apoptosis in lymphoma cells: characterisation of an internal fragment generated by caspase-3-mediated cleavage. Cell Death Differ 7: 628–636.

    Article  CAS  PubMed  Google Scholar 

  • Choi KM, McMahon LP, Lawrence Jr JC . (2003). Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor. J Biol Chem 278: 19667–19673.

    Article  CAS  PubMed  Google Scholar 

  • Chou TC . (1994). Assessment of synergistic and antagonistic effects of chemotherapeutic agents in vitro. Contrib Gynecol Obstet 19: 91–107.

    Article  CAS  PubMed  Google Scholar 

  • Chu S, Holtz M, Gupta M, Bhatia R . (2004). BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Blood 103: 3167–3174.

    Article  CAS  PubMed  Google Scholar 

  • Daley GQ, Van Etten RA, Baltimore D . (1990). Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247: 824–830.

    Article  CAS  PubMed  Google Scholar 

  • Dancey JE . (2002). Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 16: 1101–1114.

    Article  PubMed  Google Scholar 

  • Decker T, Hipp S, Ringshausen I, Bogner C, Oelsner M, Schneller F 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.

    Article  CAS  PubMed  Google Scholar 

  • Deininger MW, Druker BJ . (2003). Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev 55: 401–423.

    Article  CAS  PubMed  Google Scholar 

  • Deininger MW, Goldman JM, Lydon N, Melo JV . (1997). The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90: 3691–3698.

    CAS  PubMed  Google Scholar 

  • Deininger MW, Goldman JM, Melo JV . (2000). The molecular biology of chronic myeloid leukemia. Blood 96: 3343–3356.

    CAS  PubMed  Google Scholar 

  • Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. (2003). BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101: 690–698.

    Article  CAS  PubMed  Google Scholar 

  • Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT . (2003). Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63: 8451–8460.

    CAS  PubMed  Google Scholar 

  • Fruman DA, Ferl GZ, An SS, Donahue AC, Satterthwaite AB, Witte ON . (2002). Phosphoinositide 3-kinase and Bruton's tyrosine kinase regulate overlapping sets of genes in B lymphocytes. Proc Natl Acad Sci USA 99: 359–364.

    Article  CAS  PubMed  Google Scholar 

  • Ghaffari S, Daley GQ, Lodish HF . (1999). Growth factor independence and BCR/ABL transformation: promise and pitfalls of murine model systems and assays. Leukemia 13: 1200–1206.

    Article  CAS  PubMed  Google Scholar 

  • Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N . (1998). 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12: 502–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK et al. (2001a). Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15: 2852–2864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gingras AC, Raught B, Sonenberg N . (2001b). Regulation of translation initiation by FRAP/mTOR. Genes Dev 15: 807–826.

    Article  CAS  PubMed  Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293: 876–880.

    Article  CAS  PubMed  Google Scholar 

  • Haghighat A, Mader S, Pause A, Sonenberg N . (1995). Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J 14: 5701–5709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J . (1990). Acute leukaemia in bcr/abl transgenic mice. Nature 344: 251–253.

    Article  CAS  PubMed  Google Scholar 

  • Hentze MW . (1997). eIF4G: a multipurpose ribosome adapter? Science 275: 500–501.

    Article  CAS  PubMed  Google Scholar 

  • Hleb M, Murphy S, Wagner EF, Hanna NN, Sharma N, Park J et al. (2004). Evidence for cyclin D3 as a novel target of rapamycin in human T lymphocytes. J Biol Chem 279: 31948–31955.

    Article  CAS  PubMed  Google Scholar 

  • Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R . (2002). Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99: 3792–3800.

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Houghton PJ . (2003). Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3: 371–377.

    Article  CAS  PubMed  Google Scholar 

  • Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A et al. (2002). hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol 22: 2255–2266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacinto E, Hall MN . (2003). Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 4: 117–126.

    Article  CAS  PubMed  Google Scholar 

  • Jena N, Deng M, Sicinska E, Sicinski P, Daley GQ . (2002). Critical role for cyclin D2 in BCR/ABL-induced proliferation of hematopoietic cells. Cancer Res 62: 535–541.

    CAS  PubMed  Google Scholar 

  • Johannes G, Carter MS, Eisen MB, Brown PO, Sarnow P . (1999). Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Proc Natl Acad Sci USA 96: 13118–13123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. (2002). Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346: 645–652.

    Article  CAS  PubMed  Google Scholar 

  • Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KL . (2004). Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA 101: 18105–18110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozak M . (1991). An analysis of vertebrate mRNA sequences: intimations of translational control. J Cell Biol 115: 887–903.

    Article  CAS  PubMed  Google Scholar 

  • La Rosee P, Corbin AS, Stoffregen EP, Deininger MW, Druker BJ . (2002). Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 62: 7149–7153.

    CAS  PubMed  Google Scholar 

  • Low WK, Dang Y, Schneider-Poetsch T, Shi Z, Choi NS, Merrick WC et al. (2005). Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol Cell 20: 709–722.

    Article  CAS  PubMed  Google Scholar 

  • Lugo TG, Pendergast AM, Muller AJ, Witte ON . (1990). Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247: 1079–1082.

    Article  CAS  PubMed  Google Scholar 

  • Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST . (2003). Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 63: 5716–5722.

    CAS  PubMed  Google Scholar 

  • Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM et al. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10: 594–601.

    Article  CAS  PubMed  Google Scholar 

  • Meier-Kriesche HU, Kaplan B . (2000). Toxicity and efficacy of sirolimus: relationship to whole-blood concentrations. Clin Ther 22 (Suppl B): B93–B100.

    Article  CAS  PubMed  Google Scholar 

  • Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD et al. (2004). Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 101: 3130–3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morley SJ, Curtis PS, Pain VM . (1997). eIF4G: translation's mystery factor begins to yield its secrets. RNA 3: 1085–1104.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K et al. (2003). The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 278: 15461–15464.

    Article  CAS  PubMed  Google Scholar 

  • Notari M, Neviani P, Santhanam R, Bradley BW, Chang JS, Galietta A et al. (2005). A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation. Blood 107: 2507–2516.

    Article  PubMed  Google Scholar 

  • O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. (2003). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348: 994–1004.

    Article  CAS  PubMed  Google Scholar 

  • Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT et al. (2002). A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100: 1965–1971.

    Article  CAS  PubMed  Google Scholar 

  • Parada Y, Banerji L, Glassford J, Lea NC, Collado M, Rivas C et al. (2001). BCR-ABL and interleukin 3 promote haematopoietic cell proliferation and survival through modulation of cyclin D2 and p27Kip1 expression. J Biol Chem 276: 23572–23580.

    Article  CAS  PubMed  Google Scholar 

  • Parmar S, Smith J, Sassano A, Uddin S, Katsoulidis E, Majchrzak B et al. (2005). Differential regulation of the p70 S6 kinase pathway by interferon {alpha} and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood 106: 2436–2443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perrotti D, Turturro F, Neviani P . (2005). BCR/ABL, mRNA translation and apoptosis. Cell Death Differ 12: 534–540.

    Article  CAS  PubMed  Google Scholar 

  • Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X, Holland EC . (2003). Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 12: 889–901.

    Article  CAS  PubMed  Google Scholar 

  • Rowley JD . (1973). Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243: 290–293.

    Article  CAS  PubMed  Google Scholar 

  • Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C et al. (2004). The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10: 484–486.

    Article  CAS  PubMed  Google Scholar 

  • Sattler M, Salgia R . (1997). Activation of hematopoietic growth factor signal transduction pathways by the human oncogene BCR/ABL. Cytokine Growth Factor Rev 8: 63–79.

    Article  CAS  PubMed  Google Scholar 

  • Sawyers CL . (2003). Will mTOR inhibitors make it as cancer drugs? Cancer Cell 4: 343–348.

    Article  CAS  PubMed  Google Scholar 

  • Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG et al. (2002). Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99: 3530–3539.

    Article  CAS  PubMed  Google Scholar 

  • Schalm SS, Fingar DC, Sabatini DM, Blenis J . (2003). TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 13: 797–806.

    Article  CAS  PubMed  Google Scholar 

  • Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q et al. (2003). Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 4: 451–461.

    Article  CAS  PubMed  Google Scholar 

  • Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C et al. (2003). BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 3: 145–160.

    Article  CAS  PubMed  Google Scholar 

  • Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M et al. (2004). Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431: 200–205.

    Article  CAS  PubMed  Google Scholar 

  • Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. (2004). Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428: 332–337.

    Article  CAS  PubMed  Google Scholar 

  • Wullschleger S, Loewith R, Hall MN . (2006). TOR signaling in growth and metabolism. Cell 124: 471–484.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Drs Aimee Edinger, Hung Fan, David Fruman, Eric Stanbridge and Craig Walsh for valuable discussions about the work. We are also indebted to Drs Vitaly Polunovsky and Junia Melo for providing the protocols for the cap-binding and colony forming assays, respectively, as well as Dr Brian Druker for the kind gift of the Ba/F3-Bcr-Abl and Ba/F3-Bcr-Abl-T315I cells. Financial support: 1RO1 CA107041, 1R21 CA112936, 1R21 CA105514, RO1 EB004436, and the Waltmar Foundation.

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Authors and Affiliations

  1. The Division of Hematology/Oncology, University of California, Irvine, CA, USA

    S Prabhu, D Saadat, M Zhang, L Halbur, J P Fruehauf & S T Ong

  2. Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA

    J P Fruehauf & S T Ong

  3. Cancer Research Institute, University of California, Irvine, CA, USA

    S T Ong

  4. Center for Immunology, University of California, Irvine, CA, USA

    S T Ong

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  1. S Prabhu
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Correspondence to S T Ong.

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Prabhu, S., Saadat, D., Zhang, M. et al. A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene 26, 1188–1200 (2007). https://doi.org/10.1038/sj.onc.1209901

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