New findings published in the journal Haematologica suggest that the genesis of chronic lymphocytic leukemia (CLL) involves competition among multiple B-cell clones with special B-cell receptor features.
CLL is traditionally diagnosed by identifying a circulating B-cell clone that exceeds 5000/μL, but additional distinct clones (ADCs) have been identified in many studies, and the numbers of ADCs documented in these studies has increased along with the detection power of the various technologies used to identify them.
To better define the frequency and the characteristics of ADCs in CLL, the authors of the paper used a next-generation sequencing platform that affords high sequencing depth to analyze IGHV-IGHD-IGHJ gene rearrangements in circulating CD5+ B cells from 57 patients.
In 46 patients for whom lymphocyte count data were available, 44 had at least one ADC above the threshold of 1 B cell/μL and the average number of ADCs was 12 per patient. Moreover, in 11 patients studied longitudinally, predominant ADCs were persistent and often increased in number.
The ADCs in patients with CLL exhibited four-fold more stereotyped IGHV-IGHD-IGH rearrangements than found in CD5+ B cells from healthy individuals, and IGHV use, somatic mutations, and Ig isotype distribution were similar between the predominant ADCs and clinically relevant clones.
The findings suggest that multiple expanded clones within the CD5+ B cells is the rule rather than the exception in patients with CLL, and that leukemogenesis is a multiclonal process that likely involves competition among B cells with special B-cell receptor features.
“Taken together, our findings strongly suggest that the genesis of CLL involves multiple clones which compete for survival/expansion, with the BCR playing a role in the process,” the authors concluded. “This process could include selection for distinct abilities to respond to certain antigenic stimuli experienced by the competing B-cell clones.”
The authors further speculate that the presence of multiple ADCs might relate to clinical observations in patients with CLL who develop Richter transformation to diffuse large B-cell lymphoma or, more rarely, Hodgkin disease. Such lymphomas may originate from a distinct undetected ADC present in the patient’s clonally expanded B-cell repertoire, the authors hypothesized.
Reference
Bagnara D, Mazzarello AN, Cardente N, et al. Chronic lymphocytic leukemia often arises by a multiclonal selection process. Haematologica. 2025;110(8):1747-1757. doi:10.3324/haematol.2024.286380
