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Chronic Myeloproliferative Disorders

The ρ-kinase inhibitors Y-27632 and fasudil act synergistically with imatinib to inhibit the expansion of ex vivo CD34+ CML progenitor cells

Leukemia volume 21, pages 1708–1714 (2007)Cite this article

Abstract

Evidence from cell line-based studies indicates that ρ-kinase may play a role in the leukaemic transformation of human cells mediated by the BCR/ABL tyrosine kinase, manifest clinically as chronic myeloid leukaemia (CML). We therefore employed two separate inhibitors, Y-27632 and fasudil, to inhibit the activity of ρ-kinase against ex vivo CD34+ cells collected from patients with CML. We compared the effects of ρ-kinase inhibition in those cells with the effects of direct inhibition of BCR/ABL using the specific inhibitor imatinib. We found that inhibition of ρ-kinase inhibited the effective proliferation, and reduced survival of CML progenitor cells. When combined with imatinib, ρ-kinase inhibition added to the anti-proliferative and pro-apoptotic effects of the BCR/ABL inhibitor. Our studies may indicate therapeutic benefit in some cases for the combination of ρ-kinase inhibitors with imatinib.

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References

  1. Cortes J, Talpaz M, O'Brien S, Jones D, Luthra R, Shan J et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005; 11: 3425–3432.

    Article  CAS  PubMed  Google Scholar 

  2. Lahaye T, Riehm B, Berger U, Paschka P, Muller MC, Kreil S et al. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer 2005; 103: 1659–1669.

    Article  PubMed  Google Scholar 

  3. Unwin RD, Sternberg DW, Lu Y, Pierce A, Gilliland DG, Whetton AD . Global effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL. J Biol Chem 2005; 280: 6316–6326.

    Article  CAS  PubMed  Google Scholar 

  4. DerMardirossian C, Bokoch GM . GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol 2005; 15: 356–363.

    Article  CAS  PubMed  Google Scholar 

  5. Zhou H, Kramer RH . Integrin engagement differentially modulates epithelial cell motility by RhoA/ROCK and PAK1. J Biol Chem 2005; 280: 10624–10635.

    Article  CAS  PubMed  Google Scholar 

  6. Wiedemann A, Patel JC, Lim J, Tsun A, van Kooyk Y, Caron E . Two distinct cytoplasmic regions of the beta2 integrin chain regulate RhoA function during phagocytosis. J Cell Biol 2006; 172: 1069–1079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Salgia R, Li JL, Ewaniuk DS, Pear W, Pisick E, Burky SA et al. BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest 1997; 100: 46–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bhatia R, Munthe HA, Verfaillie CM . Role of abnormal integrin-cytoskeletal interactions in impaired beta1 integrin function in chronic myelogenous leukemia hematopoietic progenitors. Exp Hematol 1999; 27: 1384–1396.

    Article  CAS  PubMed  Google Scholar 

  9. Nicholls SE, Lucas G, Graham GJ, Russell NH, Mottram R, Whetton AD et al. Macrophage-inflammatory protein-1alpha receptor expression on normal and chronic myeloid leukemia CD34+ cells. J Immunol 1999; 162: 6191–6209.

    CAS  PubMed  Google Scholar 

  10. Davies SP, Reddy H, Caivano M, Cohen P . Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000; 351: 95–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saito H, Minamiya Y, Saito S, Ogawa J-i . Endothelial Rho and Rho kinase regulate neutrophil migration via endothelial myosin light chain phosphorylation. J Leukoc Biol 2002; 72: 829–836.

    CAS  PubMed  Google Scholar 

  12. Bhatia R, Munthe HA, Williams AD, Zhang F, Forman SJ, Slovak ML . Chronic myelogenous leukemia primitive hematopoietic progenitors demonstrate increased sensitivity to growth factor-induced proliferation and maturation. Exp Hematol 2000; 28: 1401–1412.

    Article  CAS  PubMed  Google Scholar 

  13. Melo JV, Deininger MW . Biology of chronic myelogenous leukemia – signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004; 18: 545–568.

    Article  PubMed  Google Scholar 

  14. McGahon A, Bissonnette R, Schmitt M, Cotter KM, Green DR, Cotter TG . BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood 1994; 83: 1179–1187.

    CAS  PubMed  Google Scholar 

  15. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 1994; 83: 2038–2044.

    CAS  PubMed  Google Scholar 

  16. La Rosee P, Shen L, Stoffregen EP, Deininger M, Druker BJ . No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of imatinib mesylate (Gleevec/Glivec). Hematol J 2003; 4: 413–419.

    Article  CAS  PubMed  Google Scholar 

  17. Croft DR, Olson MF . The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Mol Cell Biol 2006; 26: 4612–4627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Traycoff CM, Halstead B, Rice S, McMahel J, Srour EF, Cornetta K . Chronic myelogenous leukaemia CD34+ cells exit G0/G1 phases of cell cycle more rapidly than normal marrow CD34+ cells. Br J Haematol 1998; 102: 759–767.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E . Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci 2005; 238: 31–39.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.

    Article  CAS  PubMed  Google Scholar 

  24. Michor F . Reply: the long-term response to imatinib-treatment of CML. Br J Cancer 2007; 96: 679–680.

    Article  PubMed Central  Google Scholar 

  25. Roeder I, Horn M, Glauche I, Hochhaus A, Mueller MC, Loeffler M . Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med 2006; 10: 1181–1184.

    Article  Google Scholar 

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Authors and Affiliations

  1. Division of Laboratory and Regenerative Medicine, Stopford Building, Manchester, UK

    J Burthem & K Rees-Unwin

  2. Faculty of Life Sciences, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester, UK

    R Mottram

  3. Clinical Haematology Department, Manchester Royal Infirmary, Manchester, UK

    J Burthem, J Adams & G S Lucas

  4. Stem Cell and Leukaemia Proteomics Laboratory, University of Manchester, Manchester, UK

    E Spooncer & A D Whetton

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  1. J Burthem
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  2. K Rees-Unwin
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  7. A D Whetton
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Correspondence to J Burthem.

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Burthem, J., Rees-Unwin, K., Mottram, R. et al. The ρ-kinase inhibitors Y-27632 and fasudil act synergistically with imatinib to inhibit the expansion of ex vivo CD34+ CML progenitor cells. Leukemia 21, 1708–1714 (2007). https://doi.org/10.1038/sj.leu.2404762

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  • DOI: https://doi.org/10.1038/sj.leu.2404762

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