Abstract
The B cell receptor (BCR) is a master regulator of B cells, controlling cellular processes such as proliferation, migration and survival. Cell signalling downstream of the BCR is aberrantly activated in the B cell malignancy chronic lymphocytic leukaemia (CLL), supporting the pathophysiology of the disease. This insight has led to development and approval of small molecule inhibitors that target components of the BCR pathway. These advances have greatly improved the management of CLL, but the disease remains incurable. This may partly be explained by the inter-patient heterogeneity of the disease, also when it comes to treatment responses. Precision medicine is therefore required to optimize treatment and move towards a cure. Here, we discuss how the introduction of BCR signalling inhibitors has facilitated the development of functional in vitro assays to guide clinical treatment decisions on use of the same therapeutic agents in individual patients. The cellular responses to these agents can be analysed in high-throughput assays such as dynamic BH3 profiling, phospho flow experiments and drug sensitivity screens to identify predictive biomarkers. This progress exemplifies the positive synergy between basal and translational research needed to optimize patient care.
Highlights
Survival of the chronic lymphocytic leukaemia (CLL) cells relies on signals from the tumour microenvironment,[24,25,26] which is composed of cellular components such as monocyte-derived nurse-like cells (NLC),[27] T cells[28] and mesenchymal stromal cells.[29]
We suggest that functional precision medicine, that is the use of functional assays to identify predictive biomarkers, should be considered
Signalling through the B cell receptor (BCR) is essential for B cell survival
Summary
B cells play a key role in the adaptive immune response, which is the second line of defence against non-self pathogens. The second mechanism by which BCR signalling can be induced is by tonic BCR activation, a process which is independent of ligand engagement.[14] Several mechanisms have been proposed to account for the initiation and regulation of tonic signalling These include the self-aggregation of BCR molecules, an altered balance between constitutively active protein tyrosine kinases and protein tyrosine phosphatases, or hijacking of the BCR by the B cell activating factor of the tumour necrosis factor (TNF) family (BAFF) receptor.[15,16,17]. Survival of the CLL cells relies on signals from the tumour microenvironment,[24,25,26] which is composed of cellular components such as monocyte-derived nurse-like cells (NLC),[27] T cells[28] and mesenchymal stromal cells.[29]
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