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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.

Authors

Kathleen J. Till

John C. Allen

Fatima Talab

Ke Lin

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Dr David Allsup D.J.Allsup@hull.ac.uk
Senior Lecturer in Haematology and Honorary Consultant

Alison Bentley

Ingo Ringshausen

Andrew D. Duckworth

Andrew R. Pettitt

Nagesh Kalakonda

Joseph R. Slupsky



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.

Journal Article Type Article
Publication Date Dec 1, 2017
Journal Scientific reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 7
Issue 1
Article Number ARTN 16784
APA6 Citation Till, K. J., Allen, J. C., Talab, F., Lin, K., Allsup, D., Cawkwell, L., …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), https://doi.org/10.1038/s41598-017-17021-w
DOI https://doi.org/10.1038/s41598-017-17021-w
Keywords Multidisciplinary
Publisher URL https://www.nature.com/articles/s41598-017-17021-w

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