Parameters Involved in Autophosphorylation in Chronic Myeloid Leukemia: a Systems Biology Approach.

Himansu Kumar,Pritish Kumar Varadwaj,Swati Srivastava,Swapnil Tichkule,Saurabh Gupta,Utkarsh Raj

doi:10.7314/apjcp.2015.16.13.5273

Abstract

Chronic myeloid leukemia (CML) is a stem cell disorder characterized by the fusion of two oncogenes namely BCR and ABL with their aberrant expression. Autophosphorylation of BCR-ABL oncogenes results in proliferation of CML. The study deals with estimation of rate constant involved in each step of the cellular autophosphorylation process, which are consequently playing important roles in the proliferation of cancerous cells. A mathematical model was proposed for autophosphorylation of BCR-ABL oncogenes utilizing ordinary differential equations to enumerate the rate of change of each responsible system component. The major difficulty to model this process is the lack of experimental data, which are needed to estimate unknown model parameters. Initial concentration data of each substrate and product for BCR-ABL systems were collected from the reported literature. All parameters were optimized through time interval simulation using the fminsearch algorithm. The rate of change versus time was estimated to indicate the role of each state variable that are crucial for the systems. The time wise change in concentration of substrate shows the convergence of each parameter in autophosphorylation process. The role of each constituent parameter and their relative time dependent variations in autophosphorylation process could be inferred.

Highlights

Chronic myeloid leukemia (CML) is a hematopoietic stem cells disorder caused by translocation of 9th chromosome of ABL oncogene to 22nd chromosome of the adjacent BCR oncogene (Bayard et al, 1988; Daley et al, 1990)
To address the issue of insufficient experimental data of autophosphorylation process of Bcr-Abl pathway, we propose parameter estimation to make reliable inference of model parameters
Mass-action kinetic reactions involved in autophosphorylation process of Bcr-Abl, were mathematically modeled in the form of ordinary differential equations

Summary

Introduction

Chronic myeloid leukemia (CML) is a hematopoietic stem cells disorder caused by translocation of 9th chromosome of ABL oncogene to 22nd chromosome of the adjacent BCR oncogene (Bayard et al, 1988; Daley et al, 1990). It has been reported that Imatinib acts as an efficient inhibitor to prevent the fusion of BCR-ABL oncoprotein under the target based therapy (Marley et al, 2000) This protein acts as a kinase enzyme which aberrantly enhances the addition of phosphate group to the SH2 domain of BCR-ABL protein substrate. It has been further reported that the activity of the BCR-ABL kinase protein is dependent upon extracellular and intracellular signaling processes (Clarkson et al, 1991, Xi-Shan et al, 2014) The expression of these enzymes regulates the on/off mechanism of the cellular proliferation process in CML (Clarkson et al, 1991). Conclusions: The role of each constituent parameter and their relative time dependent variations in autophosphorylation process could be inferred

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Conclusion