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Inhibition of Bcr–Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells

Oncogene volume 21, pages 8804–8816 (2002)Cite this article

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR–ABL genetic translocation and constitutive activation of the Abl tyrosine kinase. Among members of the Signal Transducers and Activators of Transcription (STAT) family of transcription factors, Stat5 is activated by the Bcr–Abl kinase and is implicated in the pathogenesis of CML. We recently identified PD180970 as a new and highly potent inhibitor of Bcr–Abl kinase. In this study, we show that blocking Bcr–Abl kinase activity using PD180970 in the human K562 CML cell line resulted in inhibition of Stat5 DNA-binding activity with an IC50 of 5 nM. Furthermore, abrogation of Abl kinase-mediated Stat5 activation suppressed cell proliferation and induced apoptosis in K562 cells, but not in the Bcr–Abl-negative myeloid cell lines, HEL 92.1.7 and HL-60. Dominant-negative Stat5 protein expressed from a vaccinia virus vector also induced apoptosis of K562 cells, consistent with earlier studies that demonstrated an essential role of Stat5 signaling in growth and survival of CML cells. RNA and protein analyses revealed several candidate target genes of Stat5, including Bcl-x, Mcl-1, c-Myc and cyclin D2, which were down-regulated after treatment with PD180970. In addition, PD180970 inhibited Stat5 DNA-binding activity in cultured primary leukemic cells derived from CML patients. To detect activated Stat5 in CML patient specimens, we developed an immunocytochemical assay that can be used as a molecular end-point assay to monitor inhibition of Bcr–Abl signaling. Moreover, PD180970 blocked Stat5 signaling and induced apoptosis of STI-571 (Gleevec, Imatinib)-resistant Bcr–Abl-positive cells. Together, these results suggest that the mechanism of action of PD180970 involves inhibition of Bcr–Abl-mediated Stat5 signaling and provide further evidence that compounds in this structural class may represent potential therapeutic agents for CML.

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References

  • Afar D, Goga A, McLaughlin J, Witte O, Sawyers C . 1994 Science 264: 424–426

  • Benito A, Silva M, Grillot D, Nunez G, Fernandez-Luna J . 1996 Blood 87: 3837–3843

  • Besser D, Bromberg JF, Darnell JE, Hanafusa H . 1999 Mol. Cell. Biol. 19: 1401–1409

  • Bowman T, Broome M, Sinibaldi D, Wharton W, Pledger W, Sedivy J, Irby R, Yeatman T, Courtneidge S, Jove R . 2001 Proc. Natl. Acad. Sci. USA 98: 7319–7324

  • Bowman T, Garcia R, Turkson J, Jove R . 2000 Oncogene 19: 2474–2488

  • Bromberg J, Darnell JE . 2000 Oncogene 19: 2468–2473

  • Bromberg J, Horvath CM, Besser D, Lathem WW, Darnell JE . 1998 Mol. Cell. Biol. 18: 2553–2558

  • Bromberg J, Wrzeszczynska M, Devgan G, Zhao Y, Pestell R, Albanese C, Darnell JE . 1999 Cell 98: 295–303

  • Carlesso N, Frank DA, Griffin JD . 1996 J. Exp. Med. 183: 811–820

  • Catlett-Falcone R, Landowski T, Oshiro M, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna J, Nunez G, Dalton W, Jove R . 1999 Immunity 10: 105–115

  • Chai SK, Nichols GL, Rothman P . 1997 J. Immunol. 159: 4720–4728

  • Chaturvedi P, Sharma S, Reddy EP . 1997 Mol. Cell. Biol. 17: 3295–3304

  • Coffer P, Koenderman L, de Groot R . 2000 Oncogene 19: 2511–2522

  • Cortez D, Stoica G, Pierce J, Pendergast A . 1996 Oncogene 13: 2589–2594

  • Danial NN, Pernis A, Rothman P . 1995 Science 269: 1875–1877

  • Danial NN, Rothman P . 2000 Oncogene 19: 2523–2531

  • Dang C, Resar L, Emison E, Kim S, Li Q, Prescott J, Wonsey D, Zeller KL . 1999 Exp. Cell Res. 253: 63–77

  • de Groot R, Raaijmakers J, Lammers J, Jove R, Koenderman L . 1999 Blood 94: 1108–1112

  • Dorsey J, Cunnick J, Lanehart R, Huang M, Kraker A, Bhalla K, Jove R, Wu J . 2002 Leukemia 16: 1589–1595

  • Dorsey J, Jove R, Kraker A, Wu J . 2000 Cancer Res. 60: 3127–3131

  • Druker B, Sawyers C, Kantarjian H, Resta D, Reese S, Ford J, Capdeville R, Talpaz M . 2001a N. Engl. J. Med. 344: 1038–1042

  • Druker B, Talpaz M, Resta D, Peng B, Buchdunger E, Ford J, Lydon N, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers C . 2001b N. Engl. J. Med. 344: 1031–1037

  • Druker B, Tamura S, Buchdunger E, Ohno S, Segal G, Fanning S, Zimmermann J, Lydon N . 1996 Nat. Med. 2: 561–566

  • Epling-Burnette P, Liu J, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, Li Y, Wang J, Yang-Yen H, Karras J, Jove R, Loughran TJ . 2001a J. Clin. Invest. 107: 351–362

  • Epling-Burnette P, Zhong B, Bai F, Jiang K, Bailey R, Garcia R, Jove R, Djeu J, Loughran TJ, Wei S . 2001b J. Immunol. 166: 7486–7495

  • Fang G, Kim C, Perkins C, Ramadevi N, Winton E, Wittmann S, Bhalla K . 2000 Blood 96: 2246–2253

  • Frank DA, Varticovski L . 1996 Leukemia 10: 1724–1730

  • Gelfanov V, Burgess GS, Litz-Jackson S, King AJ, Marshall MS, Nakshatri H, Boswell HS . 2001 Blood 98: 2508–2517

  • Gesbert F, Griffin J . 2000 Blood 96: 2269–2276

  • Gorre M, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P, Sawyer SC . 2001 Science 293: 876–880

  • Hazlehurst L, Damiano J, Buyuksal I, Pledger W, Dalton W . 2000 Oncogene 19: 4319–4327

  • Horita M, Andreu E, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna J . 2000 J. Exp. Med. 191: 977–984

  • Ibrado A, Huang Y, Fang G, Liu L, Bhalla K . 1996 Cancer Res. 56: 4743–4748

  • Ilaria RL, Van Etten RA . 1996 J. Biol. Chem. 271: 31704–31710

  • Jain S, Susa M, Keeler M, Carlesso N, Druker B, Varticovski L . 1996 Blood 88: 1542–1550

  • Jiang K, Zhong B, Gilvary D, Corliss B, Hong-Geller E, Wei S, Djeu J . 2000 Nature Immunol. 1: 419

  • Jonuleit T, Peschel C, Schwab R, van der Kuip H, Buchdunger E, Fischer T, Huber C, Aulitzky WE . 1998 Br. J. Haematol. 100: 295–303

  • Kolibaba K, Bhat A, Heaney C, Oda T, Druker B . 1999 Leuk. Lymphoma 33: 119–126

  • Kraker A, Hartl B, Amar A, Barvian M, Showalter H, Moore C . 2000 Biochem. Pharmacol. 60: 885–898

  • Landowski T, Shain K, Oshiro M, Buyuksal I, Painter J, Dalton W . 1999 Blood 94: 265–274

  • Lin T, Mahajan S, Frank D . 2000 Oncogene 19: 2496–2503

  • Lionberger J, Wilson M, Smithgall T . 2000 J. Biol. Chem. 275: 18581–18585

  • Lord J, McIntosh B, Greenberg P, Nelson B . 2000 J. Immunol. 164: 2533–2541

  • Lugo T, Pendergast A, Muller A, Witte O . 1990 Science 247: 1079–1082

  • Mes-Masson A, McLaughlin J, Daley G, Paskind M, Witte O . 1986 Proc. Natl. Acad. Sci. USA 83: 9768–9772

  • Nagar B, Bornmann W, Pellicena P, Schindler T, Veach D, Miller T, Clarkson B, Kuriyan J . 2002 Cancer Res. 62: 4236–4243

  • Nelson KL, Rogers JA, Bowman TL, Jove R, Smithgall TE . 1998 J. Biol. Chem. 273: 7072–7077

  • Nieborowska-Skorska M, Wasik M, Slupianek A, Salomoni P, Kitamura T, Calabretta B, Skorski T . 1999 J. Exp. Med. 189: 1229–1242

  • Nimmanapalli R, O'Bryan E, Huang M, Bali P, Burnette PK, Loughran T, Tepperberg J, Jove R, Bhalla K . 2002 Cancer Res. in press

  • Obaya A, Mateyak M, Sedivy J . 1999 Oncogene 18: 2934–2941

  • Onishi M, Nosaka T, Misawa K, Mui A, Gorman D, McMahon M, Miyajima A, Kitamura T . 1998 Mol. Cell. Biol. 18: 3871–3879

  • Pendergast A, Muller A, Havlik M, Maru Y, Witte O . 1991 Cell 66: 161–171

  • Porosnicu M, Nimmanapalli R, Nguyen D, Worthington E, Perkins C, Bhalla K . 2001 Leukemia 15: 772–778

  • Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci P, Arlinghaus R, Pawson T . 1994 EMBO J. 13: 764–773

  • Reynolds J, Yang T, Qian L, Jenkinson J, Zhou P, Eastman A, Craig R . 1994 Cancer Res. 54: 6348–6352

  • Rhodes J, York R, Tara D, Tajinda K, Druker B . 2000 Exp. Hematol. 28: 305–310

  • Roumiantsev S, de Aos I, Varticovski L, Ilaria R, Van Etten R . 2001 Blood 97: 4–13

  • Rowley J . 1973 Nature 243: 290–293

  • Sawyers C, Callahan W, Witte O . 1992 Cell 70: 901–910

  • Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, Lee CK, Gerther R, Kitamura T, Frantsve J, Anastasiadou E, Loh ML, Levy DE, Ihle JN, Gilliland DG . 2000 Mol. Cell 6: 693–704

  • Sexl V, Piekorz R, Moriggl R, Rohrer J, Brown M, Bunting K, Rothammer K, Roussel M, Ihle J . 2000 Blood 96: 2277–2283

  • Sillaber C, Gesbert F, Frank D, Sattler M, Griffin J . 2000 Blood 95: 2118–2125

  • Sinibaldi D, Wharton W, Turkson J, Bowman T, Pledger W, Jove R . 2000 Oncogene 19: 5419–5427

  • Smithgall TE, Briggs SD, Schreiner S, Lerner EC, Cheng H, Wilson MB . 2000 Oncogene 19: 2612–2618

  • Socolovsky M, Fallon A, Wang S, Brugnara C, Lodish H . 1999 Cell 98: 181–191

  • Song J, Grandis J . 2000 Oncogene 19: 2489–2495

  • Sonoyama J, Matsumura I, Ezoe S, Satoh Y, Zhang X, Kataoka Y, Takai E, Mizuki M, Machii T, Wakao H, Kanakura Y . 2002 J. Biol. Chem. 277: 8076–8082

  • Thiesing J, Ohno-Jone SS, Kolibaba K, Druker B . 2000 Blood 96: 3195–3199

  • Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot R, Jove R . 1998 Mol. Cell. Biol. 18: 2545–2552

  • Wei S, Gilvary D, Corliss B, Sebti S, Sun J, Straus D, Leibson P, Trapani J, Hamilton A, Weber M, Djeu J . 2000 J. Immunol. 165: 3811

  • Wisniewski D, Lambek C, Liu C, Strife A, Veach D, Nagar B, Young M, Schindler T, Bornmann W, Bertino J, Kuriyan J, Clarkson B . 2002 Cancer Res. 62: 4244–4255

  • Yu C, Meyer D, Campbell G, Larner A, Carter-Su C, Schwartz J, Jove R . 1995 Science 269: 81–83

  • Zhou P, Qian L, Kozopas K, Craig R . 1997 Blood 89: 630–643

  • Zong CS, Zeng L, Jiang Y, Sadowski HB, Wang LH . 1998 J. Biol. Chem. 273: 28065–28072

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Acknowledgements

This work was supported by NCI grants CA55652 and CA82533 (to R Jove). We thank members of the laboratory for valuable discussions and the Moffitt Cancer Center Tumor Bank, Flow Cytometry and Molecular Imaging Core Facilities.

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Authors and Affiliations

  1. Molecular Oncology, H Lee Moffitt Cancer Center, Research Institute, Tampa, 33612, Florida, FL, USA

    Mei Huang, Jay F Dorsey, Linda B Mora, Dominic Sinibaldi, Jie Wu & Richard Jove

  2. Experimental Therapeutics, H Lee Moffitt Cancer Center, Research Institute, Tampa, 33612, Florida, FL, USA

    PK Epling-Burnette, Ramadevi Nimmanapalli, Fanqi Bai, Lynn Moscinski, William S Dalton, Kapil Bhalla & Thomas P Loughran

  3. Immunology Programs, H Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, Florida, FL, USA

    Guilian Niu, Hua Yu, Sheng Wei & Julie Djeu

  4. Department of Oncology, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Mei Huang, Jay F Dorsey, PK Epling-Burnette, Ramadevi Nimmanapalli, Linda B Mora, Guilian Niu, Dominic Sinibaldi, Fanqi Bai, Hua Yu, Lynn Moscinski, Sheng Wei, Julie Djeu, William S Dalton, Kapil Bhalla, Thomas P Loughran, Jie Wu & Richard Jove

  5. Department of Medicine, University of Arizona Health Sciences Center, Tucson, 85724, Arizona, AZ, USA

    Terry H Landowski

  6. Department of Cancer Research, Pfizer Global Research and Development, Ann Arbor, 48106, Michigan, MI, USA

    Alan Kraker

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Correspondence to Richard Jove.

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Huang, M., Dorsey, J., Epling-Burnette, P. et al. Inhibition of Bcr–Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. Oncogene 21, 8804–8816 (2002). https://doi.org/10.1038/sj.onc.1206028

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