Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome

Till, Kathleen J.; Allen, John C.; Talab, Fatima; Lin, Ke; Allsup, David; Cawkwell, Lynn; Bentley, Alison; Ringshausen, Ingo; Duckworth, Andrew D.; Pettitt, Andrew R.; Kalakonda, Nagesh; Slupsky, Joseph R.

Abstract

© 2017 The Author(s). Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome.

Citation

Till, K. J., Allen, J. C., Talab, F., Lin, K., Allsup, D., Cawkwell, L., Bentley, A., Ringshausen, I., Duckworth, A. D., Pettitt, A. R., Kalakonda, N., & Slupsky, J. R. (2017). Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome. Scientific reports, 7(1), Article ARTN 16784. https://doi.org/10.1038/s41598-017-17021-w

• Journal Article Type: Article
• Acceptance Date: Nov 21, 2017
• Online Publication Date: Dec 1, 2017
• Publication Date: Dec 1, 2017
• Deposit Date: Dec 4, 2017
• Publicly Available Date: Dec 5, 2017
• Journal: Scientific reports
• Print ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 1
• Article Number: ARTN 16784
• DOI: https://doi.org/10.1038/s41598-017-17021-w
• Keywords: Multidisciplinary
• Public URL: https://hull-repository.worktribe.com/output/485743
• Publisher URL: https://www.nature.com/articles/s41598-017-17021-w
• Contract Date: Dec 5, 2017