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Eur J Haematol. 2015 Mar;94(3):193-205. doi: 10.1111/ejh.12427. Epub 2014 Sep 13.

B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells.

Author information

1
Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

Abstract

The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

KEYWORDS:

B cell; B-cell receptor; LYN; NFκB; PI(3)K; ZAP-70; bruton tyrosine kinase; ibrutinib; miRNA; spleen tyrosine kinase

PMID:
25080849
DOI:
10.1111/ejh.12427
[Indexed for MEDLINE]

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