Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications

Nature Medicine volume 12, pages 1181–1184 (2006)Cite this article

Abstract

Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib represents a successful application of molecularly targeted cancer therapy. A rapid hematologic and cytogenetic response can be induced in the majority of people, even in advanced disease. However, complete eradication of malignant cells, which are characterized by the expression of the BCR-ABL1 fusion protein, is rare. Reasons for the persistence of the malignant clone are currently not known and provide a substantial challenge for clinicians and biologists. Based on a mathematical modeling approach that quantitatively explains a broad range of phenomena, we show for two independent datasets that clinically observed BCR-ABL1 transcript dynamics during imatinib treatment of CML can consistently be explained by a selective functional effect of imatinib on proliferative leukemia stem cells. Our results suggest the general potential of imatinib to induce a complete elimination of the malignant clone. Moreover, we predict that the therapeutic benefit of imatinib can, under certain circumstances, be accelerated by combination with proliferation-stimulating treatment strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: BCR-ABL1 transcript dynamics.
Figure 2: Model predictions for combination treatments and long-term dynamics.
Figure 3: Model scheme.

Similar content being viewed by others

References

  1. Eaves, C., Udomsakdi, C., Cashman, J., Barnett, M. & Eaves, A. The biology of normal and neoplastic stem cells in CML. Leuk. Lymphoma 11 (Suppl. 1), 245–253 (1993).

    Article  Google Scholar 

  2. Deininger, M.W., Goldman, J.M. & Melo, J.V. The molecular biology of chronic myeloid leukemia. Blood 96, 3343–3356 (2000).

    CAS  PubMed  Google Scholar 

  3. Mauro, M.J. & Druker, B.J. Chronic myelogenous leukemia. Curr. Opin. Oncol. 13, 3–7 (2001).

    Article  CAS  Google Scholar 

  4. Marley, S.B., Deininger, M.W., Davidson, R.J., Goldman, J.M. & Gordon, M.Y. The tyrosine kinase inhibitor STI571, like interferon-α, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia. Exp. Hematol. 28, 551–557 (2000).

    Article  CAS  Google Scholar 

  5. Hehlmann, R., Hochhaus, A., Berger, U. & Reiter, A. Current trends in the management of chronic myelogenous leukemia. Ann. Hematol. 79, 345–354 (2000).

    Article  CAS  Google Scholar 

  6. Cortes, J. et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin. Cancer Res. 11, 3425–3432 (2005).

    Article  CAS  Google Scholar 

  7. Druker, B.J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561–566 (1996).

    Article  CAS  Google Scholar 

  8. Holtz, M.S. et al. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99, 3792–3800 (2002).

    Article  CAS  Google Scholar 

  9. Oetzel, C. et al. The tyrosine kinase inhibitor CGP 57148 (STI 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X. Clin. Cancer Res. 6, 1958–1968 (2000).

    CAS  PubMed  Google Scholar 

  10. Vigneri, P. & Wang, J.Y. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat. Med. 7, 228–234 (2001).

    Article  CAS  Google Scholar 

  11. Topaly, J., Fruehauf, S., Ho, A.D. & Zeller, W.J. Rationale for combination therapy of chronic myelogenous leukemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning. Br. J. Cancer 86, 1487–1493 (2002).

    Article  CAS  Google Scholar 

  12. Michor, F. et al. Dynamics of chronic myeloid leukemia. Nature 435, 1267–1270 (2005).

    Article  CAS  Google Scholar 

  13. Loeffler, M. & Roeder, I. Tissue stem cells: Definition, plasticity, heterogeneity, self-organization and models—A conceptual approach. Cells Tissues Organs 171, 8–26 (2002).

    Article  Google Scholar 

  14. Roeder, I. & Loeffler, M. A novel dynamic model of hematopoietic stem cell organization based on the concept of within-tissue plasticity. Exp. Hematol. 30, 853–861 (2002).

    Article  CAS  Google Scholar 

  15. Roeder, I. et al. Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization. Blood 105, 609–616 (2005).

    Article  CAS  Google Scholar 

  16. Ichimaru, M., Tomonaga, M., Amenomori, T. & Matsuo, T. Atomic bomb and leukemia. J. Radiat. Res. (Tokyo) 32 (Suppl. 2), 14–19 (1991).

    Article  Google Scholar 

  17. O'Brien, S.G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).

    Article  CAS  Google Scholar 

  18. Müller, M.C. et al. Dynamics of BCR-ABL mRNA expression in first line therapy of chronic myelogenous leukemia patients with imatinib or interferon-α/ara-C. Leukemia 17, 2392–2400 (2003).

    Article  Google Scholar 

  19. Jorgensen, H.G., Copland, M. & Holyoake, T.L. Granulocyte–colony-stimulating factor (Filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase myelogenous leukemia. Cancer 103, 210–211 (2005).

    Article  Google Scholar 

  20. Lahaye, T. 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 103, 1659–1669 (2005).

    Article  Google Scholar 

  21. Hochhaus, A. & La Rosee, P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18, 1321–1331 (2004).

    Article  CAS  Google Scholar 

  22. Deininger, M.W. & Druker, B.J. SRCircumventing imatinib resistance. Cancer Cell 6, 108–110 (2004).

    Article  CAS  Google Scholar 

  23. Graham, S.M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

    Article  CAS  Google Scholar 

  24. Catlin, S.N., Guttorp, P. & Abkowitz, J.L. The kinetics of clonal dominance in myeloproliferative disorders. Blood 106, 2688–2692 (2005).

    Article  CAS  Google Scholar 

  25. Komarova, N.L. & Wodarz, D. Drug resistance in cancer: principles of emergence and prevention. Proc. Natl. Acad. Sci. USA 102, 9714–9719 (2005).

    Article  CAS  Google Scholar 

  26. Emig, M. et al. Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time PCR. Leukemia 13, 1825–1832 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the members of the German CML study group, coinvestigators, nursing and research staff for their collaboration and S. Fruehauf for critical reading of an earlier version of this manuscript. The modeling work (I.R., M.H., I.G. and M.L.) was partially supported by the Deutsche Forschungsgemeinschaft, grants LO-942/1-1, 2 and RO3500/1-1. Molecular and clinical studies (A.H. and M.C.M.) were supported by Novartis Pharma, the Competence Network 'Akute und chronische Leukämien' sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung, DLR e.V. – 01 GI9980/6), and the European LeukemiaNet within the Sixth European Framework Program for Research and Technology Development.

Author information

Authors and Affiliations

  1. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstrasse 16–18, Leipzig, D-04107, Germany

    Ingo Roeder, Matthias Horn, Ingmar Glauche & Markus Loeffler

  2. III. Medizinische Klinik, Fakultät für klinische Medizin Mannheim, University of Heidelberg, Wiesbadener Strasse 7–11, Mannheim, D-68305, Germany

    Andreas Hochhaus & Martin C Mueller

Authors
  1. Ingo Roeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Horn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ingmar Glauche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Hochhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin C Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus Loeffler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ingo Roeder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Simulation of CML genesis. (PDF 134 kb)

Supplementary Fig. 2

Transition characteristics. (PDF 228 kb)

Supplementary Fig. 3

Individual subject data. (PDF 587 kb)

Supplementary Fig. 4

Model prediction for combination of imatinib with cytotoxic treatment. (PDF 190 kb)

Supplementary Fig. 5

Computer simulation of prolonged imatinib administration. (PDF 192 kb)

Supplementary Table 1

Model parameters for normal and leukemic cells. (PDF 56 kb)

Supplementary Table 2

Model parameters for treatment simulation. (PDF 50 kb)

Supplementary Note (PDF 207 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roeder, I., Horn, M., Glauche, I. et al. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med 12, 1181–1184 (2006). https://doi.org/10.1038/nm1487

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1487

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing