Role of the Antigen Receptor in the Pathogenesis of B-Cell Lymphoid Malignancies

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Background

Mature B cells express on their surface Immunoglobulin molecules (IGs) [as parts of the B-cell antigen receptor (BCR)], which serve as mediators for antigen recognition. BCR IGs, together with the CD79a and CD79b heterodimer, form a signaling receptor that enables suitable molecular response to antigen stimulation. This response is “fine-tuned” by supporting environment factors.

A functional BCR is often retained in B-cell lymphoid malignancies (BLM), indicating that in most of the cases this molecule is relevant to the pathogenic mechanisms that generate and preserve the neoplastic B-cell clones. In the past 20-30 years, several lines of evidence supported the notion that the neoplastic BCR observed in a series of BLM is not an “innocent bystander” but rather is a key molecule for the selection and survival of the neoplastic cells.

Selection of B cell clones by exo-antigens dependent and/or independent mechanisms appears to operate during the first phases of the leukemogenic process as witnessed by important restrictions in the IG heavy (H) variable (V) gene repertoire observed in most BLM, with the most prominent example being Chronic Lymphocytic Leukemia (CLL). However, stimulation through the BCR remains relevant throughout the clinical course of BLM due to persistent antigenic stimulation. This concept has promoted the development of novel targeted small molecules that inhibit kinases downstream the BCR signaling pathway, which have shown strong effectiveness in many BLM even in relapsed/refractory patients.

The in-depth study of the genetic organization of the BCR IG led to the identification of unique sequence patterns that allow to spot B cells at the clonal level. These sequence patterns reside within the complementarity determining region 3 (CDR3), which is the most diverse part of the Variable (V) domain of the IGH chain. HCDR3 results from the combination of 3 different genes (IGHV, IGHD and IGHJ) and forms the 3rd H hypervariable loop located at the antigen binding site of the IG molecule. The corresponding sequence in the Light Chain (LC) of the IG generates much less diversity as the IG LC loci do not contain IGHD genes. Altogether, the sequence of the HCDR3 is sufficiently variable in terms of length and amino acid composition in order to serve as a fingerprint for identifying unique B cell clones. In addition, B cells are characterized by additional variability in the IG V domains through the introduction of somatic mutations during the affinity maturation process that culminates to the selection of antibodies fitted to recognize the stimulating antigens. These immunogenetic properties are used in molecular diagnostics to provide a precise identification of expanded B cell clones and molecular evaluation of minimal residual disease.

Nowadays, high throughput nucleotide sequencing techniques allow for the rapid identification of millions of IG rearrangements and have refined the characterization of the IGHV repertoire in various biological and clinical contexts. Although the analyses of IG rearrangements remain challenging, due to the high data complexity (different IGH/L genes, presence of somatic hypermutations and/or “indels”, variability of the HCDR3 in terms of both length and composition), there are numerous informatics tools and pipelines that provide a detailed description of IGH/LV repertoires and reliable results.

Among BLM, CLL is certainly the most paradigmatic case, where many independent studies have provided enlightening information in regard to the crucial role of the BcR IG in disease pathogenesis. These span from the skewed IGH/LV repertoire, the structure and function of the clonotypic BcR IG, to notions related to the interference of the survival and proliferation of the leukemic B cell clone through the disruption of the signaling cascade mediated by interactions between stimulating antigens and the BCR. Of particular interest, similar analyses of the normal B-cell repertoire focusing on the identification of HCDR3 motifs typically of some BLM have greatly assisted in understanding the ontogenesis of these diseases.

This research topic welcomes original research and review articles that can extend and elaborate the concepts reported above. We welcome all manuscripts related to BLM as well as pre-leukemic entities, such as monoclonal B cell lymphocytosis (MBL), which can shed new light on the topic.

In particular there is interest in the following subtopics:

IGH/LV repertoire characteristics related to human lymphoid tissues or well-defined B cell subpopulations that can provide hints on the development of BLM. These studies can be also be developed in related disease settings, such as autoimmunity or in subjects/patients in pre- or full leukemic phase.

Functional features of BCR that may allow the identification of novel molecular targets to be used in the therapy of BLM.

Keywords: B-cell antigen receptor, B-cell malignancies, lymphoid malignancies, antigen receptor, BCR IG, IGH/LV

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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