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Imatinib-dependent tyrosine phosphorylation profiling of Bcr-Abl-positive chronic myeloid leukemia cells

Leukemia volume 27, pages 743–746 (2013)Cite this article

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Bcr-Abl is the major cause and pathogenetic principle of chronic myeloid leukemia (CML). Bcr-Abl results from a chromosomal translocation that fuses the bcr and abl genes, thereby generating a constitutively active tyrosine kinase, which stimulates several signaling networks required for proliferation and survival. Bcr-Abl’s oncogenic properties comprise both a kinase and a scaffold protein.1 A number of Bcr-Abl interaction partners and downstream effectors have been described, improving our understanding of the signaling networks deranged in CML. The ‘core interactome of Bcr-Abl’ entails seven major interaction partners: GRB2, Shc1, Crk-l, c-Cbl, p85, Sts-1 and SHIP2.2

The introduction of the Bcr-Abl tyrosine kinase inhibitor (TKI) Imatinib (Gleevec) has been a landmark in the treatment of CML.3 However, the development of Imatinib resistance poses major challenges to the clinical management of CML, and although second-generation TKIs can block many Imatinib-resistant mutants they are ineffective against the common T315I mutation. An alternative strategy is to circumvent Imatinib resistance by targeting downstream pathways essential for transformation.4 Therefore, it is important to fully understand these pathways. Large-scale (phospho)proteomics experiments have addressed the phosphoproteome of Bcr-Abl-positive cells, leading to the identification of an impressive number of serine/threonine-phosphorylated sites (for example, Pan et al.5), although tyrosine-phosphorylation events remained underrepresented. However, many of the protein–protein interactions in the oncogenic Bcr-Abl network are dependent on tyrosine phosphorylation, either directly or indirectly through Bcr-Abl.2

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Acknowledgements

We like to acknowledge the Fondation Leducq: the Alliance for CamKII signaling in heart disease (CP, AS, AJRH) and the Netherlands Proteomics Centre, embedded in the Netherlands Genomics Initiative (CP, AS, AJRH), and the Science Foundation Ireland under Grant No. 06/CE/B1129 (WK) for financial support. We would like to thank Tessa Holyoake (Glasgow) for critical reading of the manuscript and helpful discussions.

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  1. C Preisinger

    Present address: 7Current address: Proteomics Facility, Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, Aachen, Germany.,

Authors and Affiliations

  1. Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    C Preisinger, O B Bleijerveld, E Corradini, A Scholten & A J R Heck

  2. Netherlands Proteomics Centre, Utrecht, The Netherlands

    C Preisinger, O B Bleijerveld, E Corradini, A Scholten & A J R Heck

  3. The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK

    J P Schwarz & K I Anderson

  4. Department of Biochemistry, RWTH Aachen University, Aachen, Germany

    P J Müller

  5. Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland

    W Kolch

  6. Centre for Biomedical Genetics, Utrecht, The Netherlands

    A J R Heck

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Preisinger, C., Schwarz, J., Bleijerveld, O. et al. Imatinib-dependent tyrosine phosphorylation profiling of Bcr-Abl-positive chronic myeloid leukemia cells. Leukemia 27, 743–746 (2013). https://doi.org/10.1038/leu.2012.243

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