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Updated: May 27, 2025

Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation

Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation

Published on: November 26, 2018

Chronic lymphocytic leukemia often arises by a multiclonal selection process.

Davide Bagnara¹, Andrea N Mazzarello², Niccolò Cardente³

¹Department of Experimental Medicine, University of Genoa, Genoa, Italy; Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY. davide.bagnara@unige.it.

|February 20, 2025

Summary

Chronic lymphocytic leukemia (CLL) diagnosis often misses additional distinct clones (ADC). Advanced sequencing revealed all CLL patients have ADCs, with an average of 12 per person, indicating a multiclonal origin for CLL.

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Area of Science:

Hematology
Immunology
Genetics

Background:

Chronic lymphocytic leukemia (CLL) is typically diagnosed by a single dominant B-cell clone exceeding 5x10^6/μL.
Previous studies suggest the presence of additional distinct clones (ADC) in CLL, with detection rates increasing with technological advancements.

Purpose of the Study:

To comprehensively define the frequency and characteristics of ADCs in CLL patients.
To investigate the clonal architecture of B-cell populations in CLL using high-depth sequencing.

Main Methods:

Employed Next Generation Sequencing (NGS) with high depth and methods to minimize overcounting.
Analyzed IGHV-IGHD-IGHJ gene rearrangements in circulating CD5+ B cells from 57 CLL patients.
Assessed lymphocyte counts and longitudinal persistence of ADCs.

Main Results:

All 57 CLL patients possessed at least one ADC alongside their clinically relevant clone (CRC).
Of 46 patients with available data, 44 had ADCs exceeding 1 B cell/μL, averaging 12 ADCs per patient.
ADCs showed increased stereotyped rearrangements compared to healthy individuals, with similar IGHV use, mutation status, and isotype distribution to CRCs.

Conclusions:

The presence of multiple expanded B-cell clones is a hallmark of CLL, suggesting leukemogenesis is a multiclonal process.
ADCs can represent distinct CLL clones or monoclonal B-cell lymphocytosis (MBL) clones.
ADCs are often persistent and can increase in number over time, highlighting the dynamic nature of clonal evolution in CLL.