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

Abstract

PURPOSE OF REVIEW Normal B cells that 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, while in some subtypes BCR expression is missing and, apparently, counterselected. Here we summarize recent the experimental evidence for the importance of BCR signaling and clinical concepts to target the BCR pathway in B cell leukemia and lymphoma. RECENT FINDINGS While 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 e.g. tonic B cell signaling, chronic (auto)-antigen exposure, and self-binding properties of the BCR. The finding that in chronic lymphocytic leukemia (CLL), BCRs bind to an epitope on the BCR itself unravels a novel concept for CLL pathogenesis. SUMMARY Targeting of the B cell receptor tyrosine kinases SYK, BTK, and PI3K 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 are required to accurately predict, which groups of patients will benefit from BCR pathway-inhibition.

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

“…[2][3][4][5][6] BCR-targeting agents have been tested in preclinical and clinical settings and demonstrated success in controlling MCL. 7,8 Remarkably, the BTK inhibitor, ibrutinib (ibr), has achieved an overall response rate of 68% and median progression-free survival of 13.9 months in relapsed and refractory patients with MCL, 9 and the drug has been approved for the treatment of MCL in this particular setting. Despite the efficacy of ibr, primary resistance presents in approximately one third of patients, and acquired resistance occurs in nearly all patients.…”

Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

“…To test whether this plasma membrane–associated fraction is functional, we asked whether it contributes to tonic or antigen-driven pre-BCR signaling by directly recruiting PI3K and Src family tyrosine kinases (SFTK), such as LYN (21, 30, 31). In both full-length and Δex2-reconstituted cells, PI3K and LYN coimmunoprecipitated with CD19, albeit less abundantly in the latter case, reflecting a much smaller pool of plasma membrane–associated Δex2.…”

BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia

“…However, the extent of BCR signaling, which represents a major driver of CLL (17,26), can be modulated by many mechanisms that are not genetically hard-wired, such as feedback loops and crosstalk with other signaling pathways (27). Consequently, one can expect a certain donor-to-donor variability of BCR signaling independent of known risk factors.…”