Targeting the B-cell receptor signaling pathway in B lymphoid malignancies

Normal B cells that have failed to productively rearrange immunoglobulin V region genes encoding a functional B-cell receptor (BCR) are destined to die. Likewise, the majority of B-cell malignancies remain dependent on functional BCR signaling, whereas in some subtypes BCR expression is missing and, apparently, counterselected. Here, we summarize the recent experimental evidence for the importance of BCR signaling and clinical concepts to target the BCR pathway in B-cell leukemia and lymphoma.

Although the dependency on pre-BCR signaling in pre-B acute lymphoblastic leukemia (ALL) seems to be limited to few ALL subtypes (e.g. TCF3-PBX1), most mature B-cell lymphomas rely on BCR signaling provided by different stimuli, for example tonic B-cell signaling, chronic (auto)-antigen exposure, and self-binding properties of the BCR. The finding that in chronic lymphocytic leukemia, BCRs bind to an epitope on the BCR itself unravels a novel concept for chronic lymphocytic leukemia pathogenesis.

Targeting of the B-cell receptor tyrosine kinases spleen tyrosine kinase, Bruton's tyrosine kinase, and phosphatidylinositol 3-kinase achieve promising clinical responses in various mature B-cell malignancies and might also be useful in defined subsets of ALL. However, further understanding of the BCR signal integration in the different disease groups is required to accurately predict which groups of patients will benefit from BCR pathway inhibition.