The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance

Abstract

Summary Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies.

Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy

“…CLL, a heterogeneous hematopoietic malignancy of mature B cells, represents the most common form of leukemia among elderly adults in western countries, which, in its progressive form, is associated with serious morbidity and mortality [61]. One of the pathological features of CLL cells, which appears to be associated with the pathogenesis of the disease, is the continuous BCR signaling which regulates the survival and expansion of CLL cells [62]. Interestingly, CLL cells from different patients express a highly similar or ‘stereotypic’ BCR [63], which has been proposed to drive B-cell expansion upon recognition of an auto-antigen or antigen [62].…”

“…One of the pathological features of CLL cells, which appears to be associated with the pathogenesis of the disease, is the continuous BCR signaling which regulates the survival and expansion of CLL cells [62]. Interestingly, CLL cells from different patients express a highly similar or ‘stereotypic’ BCR [63], which has been proposed to drive B-cell expansion upon recognition of an auto-antigen or antigen [62]. Consistent with the constitutive BCR signaling, CLL cells express higher levels of signaling proteins including Lyn, Syk, Btk, PLC-γ2, STAT3, and Erk1/2 [64,65,66,67].…”

A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma

“…3F). Importantly, we did not observe any signi cant effects on cell viability in non-hematopoietic cell lines such as NIH 3T3, NL20, and HEK-293 (Fig S3 CLL is a leukemia in which constitutive signaling through the BCR pathway is important to malignant Bcell survival (23,24). While the expression of Lck varies among primary CLL samples (4, 9, 10), both Lck and Lyn were readily detectable by western blot analysis (Fig.…”

Characterization of the Intra-tumoral B Cell Immunoglobulin Repertoire Is of Prognostic Value for Esophageal Squamous Cell Carcinoma

“…Taking advantage of bioinformatics software development and sequencing reagent optimization, the application of RNA-seq has extend to BCR analysis with high fidelity ( 20 , 23 , 29 , 31 ). High levels of tumor-infiltrating B cells exist in many cancer types and have shown both positive and negative associations with clinical outcomes ( 17 , 24 , 32 , 41 , 42 ). Though the TME of ESCC has been analyzed in several single cell sequencing studies ( 14 , 15 ), BCR characterization in the ESCC TME and its clinical association has not been investigated in large numbers of patient samples.…”