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.
Highlights
Chronic lymphocytic leukemia (CLL) is a chronic B-cell malignancy, the most common adult hematologic malignancy in Western countries
An in-depth study of somatic hypermutations (SHM) mechanism in CLL resulted in the classification of patients in two distinct subgroups based on the SHM imprint within both the rearranged immunoglobulin heavy variable (IGHV) gene and immunoglobulin kappa/lambda variable gene (IGKV/IGLV) of the clonotypic B-cell receptor immunoglobulin (BcR IG)
Subset #1 cases display a unique transcriptional profile even when compared with other CLL cases with concordant SHM status: differentially expressed genes are implicated in apoptosis (e.g., ATM, PARP1), cell proliferation (e.g., KRAS), and oxidative processes favoring the survival of CLL cells [39]
Summary
Chronic lymphocytic leukemia (CLL) is a chronic B-cell malignancy, the most common adult hematologic malignancy in Western countries. The first striking observation concerned the fact that almost half of CLL patients utilizing the IGHV3-21 gene displayed highly similar variable heavy complementarity determining region 3 (VH CDR3) and, carried restricted, IGLV3-21-encoded light chains [13, 14].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have