A mathematical model of BCR-ABL autophosphorylation, signaling through the CRKL pathway, and Gleevec dynamics in chronic myeloid leukemia

A mathematical model is presented that describes several signaling events that occur in cells from patients with chronic myeloid leukemia, i.e. autophosphorylation of the Bcr-Abl oncoprotein and subsequent signaling through the Crkl pathway. Dynamical effects of the drug STI-571 (Gleevec) on these events are examined, and a minimal concentration for drug effectiveness is predicted by simulation. Most importantly, the model suggests that, for cells in blast crisis, cellular drug clearance mechanisms such as drug efflux pumps dramatically reduce the effectiveness of Gleevec. This is a new prediction regarding the efficacy of Gleevec. In addition, it is speculated that these resistance mechanisms might be present from the onset of disease.

[1]  J. Melo,et al.  The molecular biology of chronic myeloid leukemia. , 2000, Blood.

[2]  J. Rowley.  A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining , 1973, Nature.

[3]  R. V. van Etten,et al.  c-Abl Has High Intrinsic Tyrosine Kinase Activity That Is Stimulated by Mutation of the Src Homology 3 Domain and by Autophosphorylation at Two Distinct Regulatory Tyrosines* , 2000, The Journal of Biological Chemistry.

[4]  C. Sawyers.  Chronic myeloid leukemia. , 1999, The New England journal of medicine.

[5]  R. Stewart,et al.  Kinetic characterization of CheY phosphorylation reactions: comparison of P-CheA and small-molecule phosphodonors. , 1999, Biochemistry.

[6]  J. Melo,et al.  Cytogenetic and Molecular Genetic Aspects of Chronic Myeloid Leukaemia , 2002, Acta Haematologica.

[7]  B. Druker,et al.  Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. , 2000, Blood.

[8]  H. Kantarjian,et al.  Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. , 2002, Blood.

[9]  S. Dhut,et al.  BCR-ABL and BCR proteins: biochemical characterization and localization. , 1990, Leukemia.

[10]  M. Tomasson,et al.  Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor , 1999 .

[11]  Leon Shargel,et al.  Applied biopharmaceutics and pharmacokinetics , 1980 .

[12]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[13]  N. Heisterkamp,et al.  Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. , 1994, Blood.

[14]  Haruki Nakamura,et al.  Interaction between the Amino-terminal SH3 Domain of CRK and Its Natural Target Proteins* , 1996, The Journal of Biological Chemistry.

[15]  C. Eaves,et al.  Defective regulation of leukemic hematopoiesis in chronic myeloid leukemia. , 1998, Leukemia research.

[16]  P. Tempst,et al.  Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. , 1994, Blood.

[17]  J. Melo,et al.  MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. , 2003, Blood.

[18]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[19]  S. Pazhanisamy,et al.  Kinetic mechanism of the p38-alpha MAP kinase: phosphoryl transfer to synthetic peptides. , 2000, Biochemistry.

[20]  G. Zon,et al.  Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. , 1995, Blood.

[21]  A. Cuervo,et al.  Lysosomes, a meeting point of proteins, chaperones, and proteases , 1997, Journal of Molecular Medicine.

[22]  E. Buchdunger,et al.  In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. , 1999, Journal of the National Cancer Institute.

[23]  P. Seeburg,et al.  Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. , 2000, Science.

[24]  G. Burgess,et al.  Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells. , 1993, Blood.

[25]  G. Daley,et al.  Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. , 1990, Science.

[26]  Z. Estrov,et al.  The biology of chronic myeloid leukemia. , 1999, The New England journal of medicine.

[27]  Rainer Storn,et al.  Differential Evolution – A Simple and Efficient Heuristic for global Optimization over Continuous Spaces , 1997, J. Glob. Optim..

[28]  P. Twentyman.  Transport proteins in drug resistance: biology and approaches to circumvention , 1997, Journal of internal medicine. Supplement.

[29]  M. Warmuth,et al.  Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies , 1999, Annals of Hematology.

[30]  J. Adams,et al.  Participation of ADP dissociation in the rate-determining step in cAMP-dependent protein kinase. , 1997, Biochemistry.

[31]  Yonathan Bard,et al.  Nonlinear parameter estimation , 1974 .

[32]  B. Druker,et al.  Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. , 1994, The Journal of biological chemistry.

[33]  T. Holyoake,et al.  A comparison of normal and leukemic stem cell biology in Chronic Myeloid Leukemia , 2001 .

[34]  A. Ciechanover,et al.  The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. , 2002, Physiological reviews.

[35]  B. Druker,et al.  STI571 (Gleevec) as a paradigm for cancer therapy. , 2002, Trends in molecular medicine.

[36]  AC Eaves,et al.  Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia , 2002, Leukemia.

[37]  L. Johnson,et al.  Catalytic mechanism of phosphorylase kinase probed by mutational studies. , 1999, Biochemistry.

[38]  T. Hambuch,et al.  The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  B. Druker,et al.  Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. , 2000, The Journal of pharmacology and experimental therapeutics.

[40]  R. Pazdur,et al.  Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[41]  Twentyman Pr.  Transport proteins in drug resistance: biology and approaches to circumvention. , 1997 .

[42]  T. Brubaker,et al.  Nonlinear Parameter Estimation , 1979 .

[43]  Thomas F. Coleman,et al.  A Subspace, Interior, and Conjugate Gradient Method for Large-Scale Bound-Constrained Minimization Problems , 1999, SIAM J. Sci. Comput..

[44]  N. Danial,et al.  Jak-STAT signaling induced by the v-abl oncogene. , 1995, Science.

[45]  Melo Jv.  The molecular biology of chronic myeloid leukaemia. , 1996 .

[46]  T. Holyoake,et al.  A comparison of normal and leukemic stem cell biology in Chronic Myeloid Leukemia , 2001, Hematological oncology.

[47]  D. Ross,et al.  Biochemical and clinical aspects of efflux pump related resistance to anti-cancer drugs. , 1998, Anticancer research.

[48]  R. V. van Etten,et al.  P210 and P190BCR/ABL Induce the Tyrosine Phosphorylation and DNA Binding Activity of Multiple Specific STAT Family Members* , 1996, The Journal of Biological Chemistry.

[49]  C. Verfaillie,et al.  Chronic myelogenous leukemia: mechanisms underlying disease progression , 2002, Leukemia.

[50]  P. Rothman,et al.  Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. , 1997, Journal of immunology.

[51]  R. Stewart,et al.  Kinetics of CheA autophosphorylation and dephosphorylation reactions. , 1994, Biochemistry.

[52]  R. Chopra,et al.  Biology of BCR-ABL. , 1999, Blood reviews.

[53]  T Pawson,et al.  Bcr‐Abl oncoproteins bind directly to activators of the Ras signalling pathway. , 1994, The EMBO journal.

[54]  G. Eytan,et al.  Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1 , 2001, British journal of haematology.

[55]  P. Roepe,et al.  The P-Glycoprotein Efflux Pump: How Does it Transport Drugs? , 1998, The Journal of Membrane Biology.