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Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571

Leukemia volume 16, pages 1154–1159 (2002)Cite this article

Abstract

The leukemogenic property of BCR-ABL in chronic myeloid leukemia (CML) is critically dependent on its protein tyrosine kinase activity. STI571 inhibits the BCR-ABL kinase activity, the growth and the viability of BCR-ABL expressing cells. In this study, we report the apoptotic effect of STI571 in combination with daunorubicin (DNR) on peripheral blood mononuclear cells from 11 CML patients and four BCR-ABL-positive cell lines: AR230, LAMA84, K562 and KCL22. Primary blast cells were identified by flow cytometry on the basis of their low CD45 expression. Nucleus fragmentation, exposure of phosphatidylserines and decrease in mitochondrial membrane potential were measured using acridine orange, FITC-annexin V and DiOC6(3), respectively, to evaluate apoptosis. On cell lines, the effect of DNR was negligible, whereas STI571 induced 10 to 35% of apoptosis in 18 h. STI571 sensitized AR230, LAMA84 and K562 cells to DNR when apoptosis was measured at the mitochondrial and membrane but not the nuclear levels. On CML blast cells, phosphatidyl serine exposure was significantly induced by both DNR and STI571 and was higher when these drugs were used in combination (P < 0.0003). However, the effects of this drug combination were only additive and no sensitization of blast cells to DNR by STI571 was observed. Interestingly, sensitization was evidenced in CML but not normal lymphocytes. These results suggest that other mechanisms additional to Bcr-Abl tyrosine kinase activity could be responsible for DNR resistance, and further investigations are needed to understand its origin.

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References

  1. Fialkow PJ, Jacobson RJ, Papayannopoulou T . Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage Am J Med 1977 63: 125–130

    Article  CAS  Google Scholar 

  2. Kurzrock R, Gutterman JU, Talpaz M . The molecular genetics of Philadelphia chromosome-positive leukemia N Engl J Med 1988 319: 990–998

    Article  CAS  Google Scholar 

  3. Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products Science 1990 274: 824–830

    Google Scholar 

  4. Konopka JB, Watanabe SM, Witte ON . An alteration of the human c-Abl protein in K562 leukemia cells unmasks associated tyrosine protein kinase activity Cell 1984 37: 1035–1042

    Article  CAS  Google Scholar 

  5. McLaughlin J, Chianese E, Witte O . In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome Proc Natl Acad Sci USA 1987 84: 6558–6562

    Article  CAS  Google Scholar 

  6. Gishizky ML, Witte ON . Initiation of deregulated growth of multipotent progenitor cells by bcr-abl in vitro Science 1992 256: 839–849

    Article  Google Scholar 

  7. Nishii K, Kabarowski JH, Gibbons DL, Griffiths SD, Tittely I, Wiedman LM, Greaves MF . BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block Oncogene 1996 13: 2225–2234

    CAS  PubMed  Google Scholar 

  8. Evans CA, Owen-Lynch PJ, Whetton AD, Dive C . Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hematopoietic cells Cancer Res 1993 53: 1735–1738

    CAS  PubMed  Google Scholar 

  9. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells Nat Med 1996 2: 561–566

    Article  CAS  Google Scholar 

  10. Deininger M, Goldman JM, Lydon NB, Melo JV . The tyrosine kinase inhibitor CGP 57148 selectively inhibits the growth of BCR-ABL-positive cells Blood 1997 90: 3691–3698

    CAS  PubMed  Google Scholar 

  11. Kawagushi Y, Jinnai I, Yagasaki F, Yakata Y, Matsuo T, Kuriyama K, Tomonaga M . Effect of a selective Abl tyrosine kinase inhibitor, STI571, on in vitro growth of BCR-ABL-positive acute lymphoblastic leukemia cells Leukemia 2001 15: 590–594

    Article  Google Scholar 

  12. Dan S, Naito M, Tsuruo T . Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR-ABL tyrosine kinase, CGP57148 Cell Death Differ 1998 5: 710–715

    Article  CAS  Google Scholar 

  13. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

    Article  CAS  Google Scholar 

  14. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M . Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N Engl J Med 2001 344: 1038–1042

    Article  CAS  Google Scholar 

  15. Lacombe F, Durrieu F, Briais A, Dumain P, Belloc F, Bascans E, Reiffers J, Boisseau MR, Bernard P . Flow cytometry CD45 gating for immunophenotyping of acute myeloid leukemia Leukemia 1997 11: 1878–1886

    Article  CAS  Google Scholar 

  16. Belaud-Rotureau MA, Durrieu F, Labroille G, Lacombe F, Fitoussi O, Agape P, Marit G, Reiffers J, Belloc F . Study of apoptosis related responses of leukemic blast cells to in vitro anthracycline treatment Leukemia 2000 14: 1266–1275

    Article  CAS  Google Scholar 

  17. Vayssiere JL, Petit X, Risler Y, Mignotte B . Commitment to apoptosis is associated with changes in mitochondrial biogenesis and activity in cell lines conditionally immortalized with simian virus 40 Proc Natl Acad Sci USA 1994 91: 11752–11756

    Article  CAS  Google Scholar 

  18. Durrieu F, Belloc F, Lacoste L, Dumain P, Chabrol J, Dachary-Prijent J, Morjani H, Boisseau MR, Reiffers J, Bernard P, Lacombe F . Caspase activation is an early event in anthracycline-induced apoptosis and allows detection of apoptotic cells before they are ingested by phagocytes Exp Cell Res 1998 240: 165–175

    Article  CAS  Google Scholar 

  19. Belloc F, Cotteret S, Labroille G, Schmit V, Jaloustre C, Dumain P, Durrieu F, Reiffers J, Boisseau MR, Bernard P, Lacombe F . Bcr-abl translocation can occur during the induction of multidrug resistance and confers apoptosis resistance on myeloid leukemic cell lines Cell Death Differ 1997 4: 806–814

    Article  CAS  Google Scholar 

  20. Vial JP, Belloc F, Dumain P, Besnard S, Lacombe F, Boisseau MR, Reiffers J, Bernard P . Study of the apoptosis induced in vitro by antitumoral drugs on leukaemic cells Leukemia Res 1997 21: 163–172

    Article  CAS  Google Scholar 

  21. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB . Inhibition of Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyridine derivative Cancer Res 1996 56: 100–104

    CAS  Google Scholar 

  22. Gambacorti-Passerini C, Le Coutre P, Mologni M, Fanelli M, Bertazzoli C, Marchesi E, Di Nicola M, Biondi A, Corneo GM, Belotti D, Pogliani E, Lydon NB . Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis Blood Cell Mol Dis 1997 23: 380–394

    Article  CAS  Google Scholar 

  23. Kuwazuru Y, Yoshimura A, Hanada S, Ichikawa M, Saito T, Uozumi K, Utsunomiya A, Arima T, Akiyama S . Expression of multidrug transport, P-glycoprotein, in chronic myelogenous leukemia cells in blast crisis Br J Haematol 1990 74: 24–29

    Article  CAS  Google Scholar 

  24. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV . Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance Blood 2000 96: 1070–1079

    CAS  PubMed  Google Scholar 

  25. Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ . Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells Blood 2000 96: 3195–3199

    CAS  PubMed  Google Scholar 

  26. Topaly J, Zeller WJ, Fruehauf S . Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells Leukemia 2001 15: 342–347

    Article  CAS  Google Scholar 

  27. Fang G, Kim CN, Perkins CL, Ramadevi N, Winton E, Wittmann S, Bhalla KN . CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs Blood 2000 96: 2246–2253

    CAS  PubMed  Google Scholar 

  28. Mitelman F . The cytogenetic scenario of chronic myeloid leukemia Leuk Lymphoma 1993 11 (Suppl. 1): 11–15

    Article  Google Scholar 

  29. Kantarjian HM, Keating MJ, Talpaz M, Walters RS, Smith TL, Cork A, McCredie KB, Freireich EJ . Chronic myelogenous leukemia in blast crisis: analysis of 242 patients Am J Med 1987 83: 445–454

    Article  CAS  Google Scholar 

  30. Ahuja H, Bar-Eli M, Advani SH, Benchimol S, Cline MJ . Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia Proc Natl Acad Sci USA 1989 86: 6783–6787

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Fondation de France, France (RT, FXM, FB) and the Leukaemia Research Fund, UK (JVM).

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Authors and Affiliations

  1. Laboratoire d'Hématologie, Hôpital Haut Lévêque, Pessac, France

    R Tabrizi, F Lacombe & F Belloc

  2. Laboratoire greffe de moelle UMRCNRS 5540, Université Victor Ségalen, Bordeaux, France

    FX Mahon, V Lagarde & J Reiffers

  3. Service des maladies du sang, Hôpital Haut Lévêque, Pessac, France

    P Cony Makhoul

  4. Novartis Pharma SA, Rueil Malmaison, France

    P Berthaud

  5. Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK

    JV Melo

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  1. R Tabrizi
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Tabrizi, R., Mahon, F., Cony Makhoul, P. et al. Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571. Leukemia 16, 1154–1159 (2002). https://doi.org/10.1038/sj.leu.2402498

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