Abstract
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.
Highlights
Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease
This hypothesis is generated from previous work[22] demonstrating that Lck is a key mediator of B cell receptor (BCR) signalling in CLL cells, and that BCR signalling strength in these cells is related to the level of this src-family kinase (SFK) that is present
Given that several proteins within the BCR signalling pathway are reported expressed at higher levels in CLL than in normal B cells[14], that some of these proteins such as Bruton’s tyrosine kinase (Btk) and Syk are therapeutic targets and that this pathway plays an important role in the pathogenesis of this disease, it is not unreasonable to postulate a correlation between expression of pathway proteins, BCR signalling strength and disease outcome
Summary
Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Considering that proteins such as Bruton’s tyrosine kinase (BTK) and Syk are therapeutic targets[17,20,21], it is possible that expression levels of other potential therapeutic targets within the BCR signalling pathway may inform on CLL prognosis In this regard Lck may be an important consideration. Inhibition of Lck either using a specific inhibitor or siRNA-mediated knockdown blocks proximal and distal BCR signalling events in CLL cells, and removes their influence on overall cell survival This phenomenon is reminiscent of the effects of 2 other BCR pathway inhibitors, idelalisib and ibrutinib, which inhibit PI3Kδ and Bruton’s tyrosine kinase (Btk), respectively[26]. Lck may be considered a biological target in the treatment of CLL in the same way targeting Btk and PI3Kδ are
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