B-cell Receptor Signalling and Its Crosstalk With Other Pathways in Normal and Malignant Cells

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Lymphoma, Follicular / drug therapy
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / metabolism*
  • Lymphoma, Follicular / pathology
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Receptor Cross-Talk*
  • Receptors, Antigen, B-Cell / antagonists & inhibitors
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction / genetics*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptors, Antigen, B-Cell
  • Protein-Tyrosine Kinases