Immunogenetic Studies of Chronic Lymphocytic Leukemia: Revelations and Speculations about Ontogeny and Clinical Evolution

Abstract

Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IG) has proved instrumental in dissecting chronic lymphocytic leukemia (CLL) pathogenesis. Initially, it was the finding that the level of somatic hypermutations in rearranged IG heavy-chain genes could define two CLL subtypes associated with a different clinical course that drew attention. As the years ensued, this not only continued to hold strong, but also revealed an unprecedented BcR restriction (aptly coined as "stereotypy"), thus cementing the idea that antigenic elements select the leukemic clones. With all this in mind, in the present review, we focus on the CLL BcR IG, a molecule that clearly lies at the heart of disease pathogenesis, and attempt to distil from past and emerging biologic knowledge the most relevant aspects in the context of the immunogenetics of CLL, while at the same time provoking questions that remain unanswered. We juxtapose CLL with mutated BcR IGs against CLL with unmutated BcR IGs due to their striking clinicobiologic differences; however, when considering ontogeny, common derivation of the two mutational subtypes cannot be excluded. The issue of stereotypy is intertwined throughout and we also raise the subject of isotype-switched CLL, which, despite its rarity, contributes intriguing ontogenetic hints. Cancer Res; 74(16); 4211-6. Ó2014 AACR.

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

“…CLL is a highly heterogeneous disease both in terms of biological features3, with leukaemic B cells ranging from functionally anergic to highly proliferating, and clinical courses varying from indolent to highly aggressive.…”

Comprehensive translocation and clonality detection in lymphoproliferative disorders by next-generation sequencing

“…Sequencing of the V-(D)-J gene rearrangements in any of the IG/TR loci can be used not only to assess clonality and enable a more indepth analysis of clonal relationships and clonal evolution, but also to identify targets for minimal residual disease monitoring and analysis of the IG/TR repertoire of diverse lymphoid populations. Additional information, for example the somatic hypermutation status of the IGHV-IGHD-IGHJ gene rearrangements, relevant for prognosis in CLL 6 can also be obtained. A new version of this EuroClonality-NGS panel is being designed to include common non-IG/TR translocations as well as genes relevant for diagnosis and prognosis in LPD and a clinical multicenter validation study is now underway within the EuroClonality-NGS consortium.…”

“…6 Until recently, collecting this information required a combination of different methodologies, such as gene-scanning/heteroduplex analysis, fluorescence in situ hybridization (FISH) and Sanger sequencing. The incorporation of next-generation sequencing (NGS) in clinical laboratories opens up new possibilities since an integrated NGS approach can provide data on sequence and structural variation in a single assay, including translocations and IG/TR rearrangements, and has been shown to be successful for the characterisation of IG translocations in myeloma and lymphomas.…”

The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

“…15,16 In contrast, somatic mutations in genes encoding components of the BCR signaling pathway are uncommon in CLL. 17 During development, each B cell recombines immunoglobulin variable (V), diversity (D), and BCR activation induces expression of the enzyme adenosine deaminase (AID) which introduces somatic mutations into the gene segments encoding the variable domain of the BCR.…”

“…However, the cellular derivation of CLL cells is more complex, and there is good evidence that antigen selection plays a role in both CLL subtypes. 15,16,116 A B and autoantigens. 15 In addition, the BCR of many CLL cells recognizes an epitope that is part of the CLL BCR itself, possibly contributing to auto-stimulation on a single cell level.…”