Abstract
Advanced genome-wide association studies (GWAS) identified several transforming mutations in susceptible loci which are recognized as valuable prognostic markers in chronic lymphocytic leukemia (CLL) and B cell lymphoma (BCL). Alongside, robust genetic manipulations facilitated the generation of preclinical mouse models to validate mutations associated with poor prognosis and refractory B cell malignancies. Taken together, these studies identified new prognostic markers that could achieve characteristics of precision biomarkers for molecular diagnosis. On the contrary, the idea of augmented B cell antigen receptor (BCR) signaling as a transforming cue has somewhat receded despite the efficacy of Btk and Syk inhibitors. Recent studies from several research groups pointed out that acquired mutations in BCR components serve as faithful biomarkers, which become important for precision diagnostics and therapy, due to their relevant role in augmented BCR signaling and CLL pathogenesis. For example, we showed that expression of a single point mutated immunoglobulin light chain (LC) recombined through the variable gene segment IGLV3-21, named IGLV3-21R110, marks severe CLL cases. In this perspective, we summarize the molecular mechanisms fine-tuning B cell transformation, focusing on immunoglobulin point mutations and recurrent mutations in tumor suppressors. We present a stochastic model for gain-of-autonomous BCR signaling and subsequent neoplastic transformation. Of note, additional mutational analyses on immunoglobulin heavy chain (HC) derived from non-subset #2 CLL IGLV3-21R110 cases endorses our perspective. Altogether, we propose a model of malignant transformation in which the augmented BCR signaling creates a conducive platform for the appearance of transforming mutations.
Highlights
The B cell antigen receptor (BCR) signaling is the key survival and growth promoter for both normal and malignant B cells, controlling important cell fate decisions including proliferation and differentiation [1]
We review the current understanding of BCR associated biomarker exemplifying a novel IGL mutation, termed IGLV321R110, in severe pathogenesis including stereotypic chronic lymphocytic leukemia (CLL) subset #2 [26,27,28]
We demonstrate that the survival signal is sustained by the gain-of-autonomous BCR signaling attained through point mutations in IGLV and IGHV genes (Figure 2) [27]
Summary
The B cell antigen receptor (BCR) signaling is the key survival and growth promoter for both normal and malignant B cells, controlling important cell fate decisions including proliferation and differentiation [1]. We show that the gain-of-autonomous BCR signaling requires point mutations in both IGLV and IGHV genes derived from a non-subset #2 CLL IGLV3-21R110 case. The recent finding of higher-order correlation between several major and minor CLL subsets are in line with the IGLV3-21R110 based broader classification which is best exemplified by CLL subset #2 and #169 [27, 41] Both stereotyped subsets employ the IGLV3-21R110 light chain and display structural and immunogenetic similarities with severe clinical courses suggesting a common antigen selection process in their pathogenesis [45]. B cell specific double transgenic mice overexpressing antiapoptotic Bcl-2 and dominant negative form Traf adapter develop CLL/SLL-like phenotype with restricted IGHV usage mimicking CLL BCR stereotypes [59] This model suggests a conducive role of anti-apoptosis, allowing either selection of BCR clones from an indolent pool or escape of autoreactive clones from the self-elimination process. The appearance of further recurrent mutations in genes such as SF3B1 and TP53 accelerate and exacerbate the disease when combined with permissive BCR signaling or other conducive features resembling a stochastic process
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