Figure 2.

The B-cell receptor (BCR) is a central mediator of malignant B-cell homing, survival and EMDR. B-cell homing to the bone marrow and/or secondary lymphoid organs as well as niches within these tissues is controlled by the dynamic interplay between chemokine networks and cellular adhesion molecule. The BCR regulates the interplay between ‘outside-in’ and ‘inside-out’ signaling by CXCR4 and VLA-4 (α4/β1 integrin heterodimers). As such, the BCR is positioned as a central modulator of homing, environment-mediated drug resistance (EMDR), MRD, eventual therapy resistance and relapse within the context of the TME. Continuous BCR signaling within the context of the TME modulates key extrinsic and intrinsic pathways. BCR signaling mediates the inside-out activation of α4/β1 integrins facilitating B-cell adhesion. BCR signaling components Bruton's tyrosine kinase (BTK) and phospholipase C (PLC)-γ2 are targets of outside-in activation by the CXCL12/SDF-1 and integrins promoting B-cell migration and adhesion. These observations suggest a role for the BCR at the crossroads of key components of malignant B-cell homing within the TME. This hypothesis is further supported by the striking responses in B-cell disorders treated with BCR signaling inhibitors specifically targeting BTK, SYK and PI3Kδ alone and in combination with cytotoxic agents. It is apparent that the TME also influences the BCR signaling.