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Discrete and Continuous Dynamical Systems - Series B (DCDS-B)
 

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

Pages: 99 - 114, Volume 4, Issue 1, February 2004      doi:10.3934/dcdsb.2004.4.99

 
       Abstract        Full Text (281.0K)       Related Articles

Pep Charusanti - Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States (email)
Xiao Hu - Biocybernetics Laboratory, Departments of Computer Science and Medicine, University of California, Los Angeles, Los Angeles, California 90095-1596, United States (email)
Luonan Chen - Biocybernetics Laboratory, Departments of Computer Science and Medicine, University of California, Los Angeles, Los Angeles, California 90095-1596, United States (email)
Daniel Neuhauser - Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States (email)
Joseph J. DiStefano III - Biocybernetics Laboratory, Departments of Computer Science and Medicine, University of California, Los Angeles, Los Angeles, California 90095-1596, United States (email)

Abstract: 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.

Keywords:  Chronic myeloid leukemia, Bcr-Abl, Gleevec, clearance, autophosphorylation.
Mathematics Subject Classification:  92C45, 92B05.

Received: November 2002;      Revised: June 2003;      Available Online: November 2003.