Journal of Molecular Medicine

, Volume 86, Issue 1, pp 17–27

Pathogenesis, treatment effects, and resistance dynamics in chronic myeloid leukemia - insights from mathematical model analyses

Review
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Abstract

Mathematical models and simulation studies are powerful tools to investigate dynamic properties of complex systems. Specifically, they can be used to test alternative hypotheses on underlying biological mechanisms for their consistency with real data and therefore to effectively guide the design of new experimental strategies or clinical trials. In this study, we present an overview of recently published mathematical approaches applied to the description of chronic myeloid leukemia (CML). We discuss three different fields relevant to clinical issues: the pathogenesis of the malignancy, the treatment effects of the tyrosine kinase inhibitor imatinib, and the process of acquired treatment resistance highlighting both the differences and the consistencies in the proposed hypotheses and the resulting conclusions. The mathematical models presented agree that CML can adequately be described as a clonal competition between normal and leukemic stem cells for a common resource. Furthermore, a certain therapeutic effect of imatinib on leukemic stem cells turned out to be necessary to consistently explain clinical data on the long-term response of CML patients under imatinib treatment. However, the approaches described cannot resolve the question whether or not this effect is sufficient to ultimately eradicate malignant stem cells. A number of different hypotheses have been proposed concerning the initiation and the dynamics of treatment-resistant malignant stem cell clones. The theoretical results clearly indicate that further experimental effort with the particular focus on the quantitative monitoring of resistant clones will be required to definitely distinguish between these hypotheses.

Keywords

Chronic myeloid leukemia (CML) Imatinib treatment Resistant clone dynamics Mathematical model Simulation analysis 

References

  1. 1.
    Viswanathan S, Zandstra PW (2003) Towards predictive models of stem cell fate. Cytotechnology 4:75–92CrossRefGoogle Scholar
  2. 2.
    Roeder I (2006) Quantitative stem cell biology: computational studies in the hematopoietic system. Curr Opin Hematol 13:222–228PubMedCrossRefGoogle Scholar
  3. 3.
    Loeffler M, Roeder I (2004) Conceptual models to understand tissue stem cell organization. Curr Opin Hematol 11:81–87PubMedCrossRefGoogle Scholar
  4. 4.
    Michor F, Iwasa Y, Nowak MA (2004) Dynamics of cancer progression. Nat Rev Cancer 4:197–205PubMedCrossRefGoogle Scholar
  5. 5.
    Deininger MW, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia in process citation. Blood 96:3343–3356PubMedGoogle Scholar
  6. 6.
    Mauro MJ, Druker BJ (2001) Chronic myelogenous leukemia. Curr Opin Oncol 13:3–7PubMedCrossRefGoogle Scholar
  7. 7.
    Holyoake TL, Jiang X, Jorgensen HG, Graham S, Alcorn MJ, Laird C et al (2001) Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood 97:720–728PubMedCrossRefGoogle Scholar
  8. 8.
    Chai SK, Nichols GL, Rothman P (1997) Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol 159:4720–4728PubMedGoogle Scholar
  9. 9.
    Tauchi T, Ohyashiki K (2004) Imatinib mesylate in combination with other chemotherapeutic agents for chronic myelogenous leukemia. Int J Hematol 79:434–440PubMedCrossRefGoogle Scholar
  10. 10.
    Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G et al (1995) Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood 86:726–736PubMedGoogle Scholar
  11. 11.
    Ilaria RL Jr, Van Etten RA (1996) P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 271:31704–31710PubMedCrossRefGoogle Scholar
  12. 12.
    Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C (1999) Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci U S A 96:12804–12809PubMedCrossRefGoogle Scholar
  13. 13.
    Cheng K, Kurzrock R, Qiu X, Estrov Z, Ku S, Dulski KM et al (2002) Reduced focal adhesion kinase and paxillin phosphorylation in BCR-ABL-transfected cells. Cancer 95:440–450PubMedCrossRefGoogle Scholar
  14. 14.
    Verfaillie CM, Hurley R, Lundell BI, Zhao C, Bhatia R (1997) Integrin-mediated regulation of hematopoiesis: do BCR/ABL-induced defects in integrin function underlie the abnormal circulation and proliferation of CML progenitors. Acta Haematol 97:40–52PubMedCrossRefGoogle Scholar
  15. 15.
    Deutsch E, Dugray A, AbdulKarim B, Marangoni E, Maggiorella L, Vaganay S et al (2001) BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood 97:2084–2090PubMedCrossRefGoogle Scholar
  16. 16.
    Slupianek A, Schmutte C, Tombline G, Nieborowska-Skorska M, Hoser G, Nowicki MO et al (2001) BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. Mol Cell 8:795–806PubMedCrossRefGoogle Scholar
  17. 17.
    Kantarjian HM, Talpaz M, Giles F, O’ Brien S, Cortes J (2006) New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med 145:913–923PubMedGoogle Scholar
  18. 18.
    Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653PubMedCrossRefGoogle Scholar
  19. 19.
    Hehlmann R (2003) Current CML therapy: progress and dilemma. Leukemia 17:1010–1012PubMedCrossRefGoogle Scholar
  20. 20.
    Borthakur G, Cortes JE (2004) Imatinib mesylate in the treatment of chronic myelogenous leukemia. Int J Hematol 79:411–419PubMedCrossRefGoogle Scholar
  21. 21.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289:1938–1942PubMedCrossRefGoogle Scholar
  22. 22.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566PubMedCrossRefGoogle Scholar
  23. 23.
    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 99:3792–3800PubMedCrossRefGoogle Scholar
  24. 24.
    Oetzel C, Jonuleit T, Gotz A, Kuip Hvd, Michels H, Duyster J et al (2000) The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X. Clin Cancer Res 6:1958–1968PubMedGoogle Scholar
  25. 25.
    Vigneri P, Wang JY (2001) Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 7:228–234PubMedCrossRefGoogle Scholar
  26. 26.
    Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99:319–325PubMedCrossRefGoogle Scholar
  27. 27.
    Holtz MS, Forman SJ, Bhatia R (2005) Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia 19:1034–1041PubMedCrossRefGoogle Scholar
  28. 28.
    Holtz M, Forman SJ, Bhatia R (2007) Growth factor stimulation reduces residual quiescent chronic myelogenous leukemia progenitors remaining after imatinib treatment. Cancer Res 67:1113–1120PubMedCrossRefGoogle Scholar
  29. 29.
    Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417PubMedCrossRefGoogle Scholar
  30. 30.
    Roy L, Guilhot J, Krahnke T, Guerci-Bresler A, Druker BJ, Larson RA et al (2006) Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 108:1478–1484PubMedCrossRefGoogle Scholar
  31. 31.
    Ritchie E, Nichols G (2006) Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy. Curr Cancer Drug Targets 6:645–657PubMedCrossRefGoogle Scholar
  32. 32.
    Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T et al (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16:2190–2196PubMedCrossRefGoogle Scholar
  33. 33.
    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 293:876–880PubMedCrossRefGoogle Scholar
  34. 34.
    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 101:690–698PubMedCrossRefGoogle Scholar
  35. 35.
    Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L et al (2000) Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst 92:1641–1650PubMedCrossRefGoogle Scholar
  36. 36.
    Kiem HP, Sellers S, Thomasson B, Morris JC, Tisdale JF, Horn PA et al (2004) Long-term clinical and molecular follow-up of large animals receiving retrovirally transduced stem and progenitor cells: no progression to clonal hematopoiesis or leukemia. Mol Ther 9:389–395PubMedCrossRefGoogle Scholar
  37. 37.
    Bornhauser M, Illmer T, Le Coutre P, Pursche J, Bonin Mv, Freiberg-richter J et al (2004) Imatinib mesylate selectively influences the cellular metabolism of cytarabine in BCR/ABL negative leukemia cell lines and normal CD34+ progenitor cells. Ann Hematol 83(Suppl 1):61–64Google Scholar
  38. 38.
    Azam M, Latek RR, Daley GQ (2003) Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112:831–843PubMedCrossRefGoogle Scholar
  39. 39.
    O’Hare T, Corbin AS, Druker BJ (2006) Targeted CML therapy: controlling drug resistance, seeking cure. Curr Opin Genet Dev 16:92–99PubMedCrossRefGoogle Scholar
  40. 40.
    Catlin SN, Guttorp P, Abkowitz JL (2005) The kinetics of clonal dominance in myeloproliferative disorders. Blood 106:2688–2692PubMedCrossRefGoogle Scholar
  41. 41.
    Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL et al (2005) Dynamics of chronic myeloid leukaemia. Nature 435:1267–1270PubMedCrossRefGoogle Scholar
  42. 42.
    Dingli D, Michor F (2006) Successful therapy must eradicate cancer stem cells. Stem Cells 24:2603–2610PubMedCrossRefGoogle Scholar
  43. 43.
    Roeder I, Horn M, Glauche I, Hochhaus A, Mueller MC, Loeffler M (2006) Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med 12:1181–1184PubMedCrossRefGoogle Scholar
  44. 44.
    Michor F (2007) Reply: the long-term response to imatinib treatment of CML. Br J Cancer 96:679–680CrossRefGoogle Scholar
  45. 45.
    Glauche I, Horn M, Roeder I (2007) Leukaemia stem cells: hit or miss? Br J Cancer 96:677–678 author reply 679–680)PubMedCrossRefGoogle Scholar
  46. 46.
    Cheshier SH, Morrison SJ, Liao X, Weissman IL (1999) In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci U S A 96:3120–3125PubMedCrossRefGoogle Scholar
  47. 47.
    Bradford GB, Williams B, Rossi R, Bertoncello I (1997) Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol 25:445–453PubMedGoogle Scholar
  48. 48.
    Jorgensen HG, Copland M, Holyoake TL (2005) Granulocyte–colony-stimulating factor (Filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase myelogenous leukemia. Cancer 103:210–211PubMedCrossRefGoogle Scholar
  49. 49.
    Jorgensen HG, Copland M, Allan EK, Jiang X, Eaves A, Eaves C et al (2006) Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 12:626–633PubMedCrossRefGoogle Scholar
  50. 50.
    Hochhaus A, Reiter A, Reichert SS, Emig M, Kaeda J, Schultheis B et al (2000) Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. Blood 95:62–66PubMedGoogle Scholar
  51. 51.
    Hochhaus A, Weisser A, La Rosee P, Emig M, Muller MC, Saussele S et al (2000) Detection and quantification of residual disease in chronic myelogenous leukemia. Leukemia 14:998–1005PubMedCrossRefGoogle Scholar
  52. 52.
    Goldman J (2005) Monitoring minimal residual disease in BCR-ABL-positive chronic myeloid leukemia in the imatinib era. Curr Opin Hematol 12:33–39PubMedCrossRefGoogle Scholar
  53. 53.
    Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–125PubMedCrossRefGoogle Scholar
  54. 54.
    Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai JL, Philippe N, Facon T et al (2002) Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100:1014–1018PubMedCrossRefGoogle Scholar
  55. 55.
    Muller MC, Lahaye T, Hochhaus A (2002) Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells. Dtsch Med Wochenschr 127:2205–2207PubMedCrossRefGoogle Scholar
  56. 56.
    Liu NS, O’Brien S (2002) Spontaneous reversion from blast to chronic phase after withdrawal of imatinib mesylate in a patient with chronic myelogenous leukemia. Leuk Lymphoma 43:2413–2415PubMedCrossRefGoogle Scholar
  57. 57.
    Komarova NL, Wodarz D (2005) Drug resistance in cancer: principles of emergence and prevention. Proc Natl Acad Sci U S A 102:9714–9719PubMedCrossRefGoogle Scholar
  58. 58.
    Wodarz D, Komarova NL (2005) Emergence and prevention of resistance against small molecule inhibitors. Semin Cancer Biol 15:506–514PubMedCrossRefGoogle Scholar
  59. 59.
    Iwasa Y, Michor F, Nowak MA (2003) Evolutionary dynamics of escape from biomedical intervention. Proc Biol Sci 270:2573–2578PubMedCrossRefGoogle Scholar
  60. 60.
    Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D et al (2005) High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 106:2128–2137PubMedCrossRefGoogle Scholar
  61. 61.
    Gruber FX, Lamark T, Anonli A, Sovershaev MA, Olsen M, Gedde-Dahl T et al (2005) Selecting and deselecting imatinib-resistant clones: observations made by longitudinal, quantitative monitoring of mutated BCR-ABL. Leukemia 19:2159–2165PubMedCrossRefGoogle Scholar
  62. 62.
    Khorashad JS, Anand M, Marin D, Saunders S, Al-Jabary T, Iqbal A et al (2006) The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia 20:658–663PubMedCrossRefGoogle Scholar
  63. 63.
    Soverini S, Martinelli G, Amabile M, Poerio A, Bianchini M, Rosti G et al (2004) Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to Imatinib. Clin Chem 50:1205–1213PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Institute for Medical Informatics, Statistics and Epidemiology (IMISE)University of LeipzigLeipzigGermany

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