Distinctive Signaling Profiles With Distinct Biological and Clinical Implications in Aggressive CLL Subsets With Stereotyped B-Cell Receptor Immunoglobulin

Abstract

The ontogeny and evolution of chronic lymphocytic leukemia (CLL) are critically dependent on interactions between leukemic cells and their microenvironment, including antigens, the latter recognized through the clonotypic B-cell receptor immunoglobulin (BcR IG). Antigen selection is key to the pathogenesis of CLL, as evidenced by the remarkable skewing of the BcR IG gene repertoire, culminating in BcR IG stereotypy, referring to the existence of subsets of patients with (quasi)identical BcR IG. Notably, certain of these subsets have been found to display distinct, subset-biased biological background, clinical presentation, and outcome, including the response to treatment. This points to BcR IG centrality while also emphasizing the need to dissect the signaling pathways triggered by the distinctive BcR IG expressed by different subsets, particularly those with aggressive clinical behavior. In this mini-review, we discuss the current knowledge on the implicated signaling pathways as well as the recurrent gene mutations in these pathways that characterize major aggressive stereotyped subsets. Special emphasis is given on the intertwining of BcR IG and Toll-like receptor (TLR) signaling and the molecular characterization of signaling activation, which has revealed novel players implicated in shaping clinical aggressiveness in CLL, e.g., the histone methyltransferase EZH2 and the transcription factor p63.

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

“…Each subset displays common genomic abnormalities ( 21 ) as well as highly homogeneous clinical and biological properties ( 22 ). Altogether, the IGHV-D-J gene recombination pattern and the amino acid constitution of the heavy chain variable complementarity determining region 3 (HCDR3) categorize these stereotyped CLL cases into 19 major subgroups ( 1 , 22 , 23 ). Very recently, a detailed study on BCR stereotypy reported that not only 30% but even 41% of all CLL cases can be categorized into stereotypic subgroups with overall 29 major subsets ( 20 ).…”

Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

“…The antigen-dependent activation is subordinate to the binding of self or exogenous antigens to the BCR, whereas the antigen-independent signaling is initiated by the Ig-Ig interaction within the membrane of the same cell, rather than by activating mutations of the signaling pathway molecules (such as CARD11, CD79a, and CD79b), which appear to be rare [43,44]. Furthermore, ~30% of CLL carries quasi-identical VDJ rearrangement of BCR Ig across different patients, which are groupable in stereotyped subsets, identified by a progressive numbering [45,46]. Remarkably, BCR subset 8, characterized by the IGHV4-39/IGHD6-13/IGHJ5 asset, is frequently associated with peculiar genetic lesions (namely, trisomy 12 and NOTCH1 mutations) linked to aggressive disease and progression of CLL into DLBCL-type RS, which is more common among patients carrying this specific BCR stereotype [7,47,48].…”

Immunoglobulin Gene Sequence as an Inherited and Acquired Risk Factor for Chronic Lymphocytic Leukemia

“…In the past 20 years, huge initiatives have been taken to categorize the sequence information of different CLL cases from different parts of the world. With the increasing ease of sequencing and the advent of automated bioinformatic tools to annotate them, it is now possible to classify the CLL cases (one-third of all CLL cases that belongs to stereotyped CLL) into 19 major subsets depending on the IGHV-D-J gene recombination pattern and the length and amino acid composition at the heavy-chain variable complementarity determining region 3 (HCDR3) (reviewed in [2,39,41]). Remarkably, the members of each subset share common disease features such as genetic mutations, chromosomal abnormalities, epigenetic condition, gene expression profiles, defects in certain signal transduction pathways, and most importantly, the clinical prognosis and outcome.…”