Mathematical modelling of miRNA mediated BCR.ABL protein regulation in chronic myeloid leukaemia vis-a-vis therapeutic strategies

Malkhey Verma; Ehsan Ghayoor Karimiani; Richard J. Byers; Samrina Rehman; Hans V. Westerhoff; Philip J. R. Day

doi:10.1039/C3IB20230E

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Corresponding authors

Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, School for Chemical Engineering and Analytical Science, University of Manchester, Manchester, UK
E-mail: malkhey.verma@manchester.ac.uk, samrina.rehman@manchester.ac.uk

Quantitative Molecular Medicine Research, Faculty of Medical and Human Sciences, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
E-mail: philip.j.day@manchester.ac.uk

Department of New Sciences and Technology, Mashhad University of Medical Sciences, Mashhad, Iran

Dept of Histopathology, Manchester Royal Infirmary, Manchester, UK
E-mail: r.byers@manchester.ac.uk

Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK

Synthetic Systems Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands

Department of Molecular Cell Biology, Netherlands Institute for Systems Biology, VU University Amsterdam, Amsterdam, Netherlands
E-mail: h.v.westerhoff@uva.nl

Doctoral Training Centre ISBML, The Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, UK

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Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disease resulting from an aberrant BCR.ABL gene and protein. To predict BCR.ABL protein abundance and phosphorylation in individual cells in a population of CML cells, we modelled BCR.ABL protein regulation through associated miRNAs using a systems approach. The model rationalizes the level of BCR.ABL protein heterogeneity in CML cells in correlation with the heterogeneous BCR.ABL mRNA levels. We also measured BCR.ABL mRNA and BCR.ABLp phosphorylation in individual cells. The experimental data were consistent with the modelling results, thereby partly validating the model. Provided it is tested further, the model may be used to support effective therapeutic strategies including the combined application of a tyrosine kinase inhibitor and miRNAs targeting BCR.ABL. It appears able to predict different effects of the two types of drug on cells with different expression levels and consequently different effects on the generation of resistance.

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Malkhey Verma
Ehsan Ghayoor Karimiani
Richard J. Byers
Samrina Rehman
Hans V. Westerhoff
Philip J. R. Day

Integrative Biology