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Updated: Oct 3, 2025
Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
Published on: November 26, 2018
Biological and Clinical Insight from Analysis of the Tumor B-Cell Receptor Structure and Function in Chronic
Francesco Forconi1,2, Stuart A Lanham1, Giorgia Chiodin1
1School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton SO16 6YD, UK.
Insights
Chronic lymphocytic leukemia (CLL) B-cell receptor (BCR) signaling varies, impacting disease progression and treatment resistance. Understanding B-cell receptor (BCR) expression is key to managing CLL behavior and therapy effectiveness.
Area of Science:
- Hematology
- Immunology
- Oncology
Background:
- The B-cell receptor (BCR) is crucial for B-cell function in both normal and cancerous states.
- Chronic lymphocytic leukemia (CLL) is characterized by two main subsets: unmutated IGHV (U-CLL) and mutated IGHV (M-CLL), with distinct prognoses.
- BCR signaling research has yielded critical insights into CLL biology and led to targeted therapies.
Purpose of the Study:
- To investigate the role of B-cell receptor (BCR) structure and function in CLL.
- To understand the variability of surface IgM (sIgM) expression in CLL and its impact on disease behavior.
- To explore how sIgM levels influence therapeutic responses, particularly for Bruton's tyrosine kinase (BTK) inhibitors.
Main Methods:
- Analysis of immunoglobulin (Ig) variable region genes (IGHV) to classify CLL subsets.
- Assessment of surface IgM (sIgM) expression levels on CLL cells.
- Correlation of sIgM levels with clinical course and treatment outcomes.
Main Results:
- U-CLL and M-CLL subsets exhibit variable sIgM expression and signaling capacity.
- sIgM variability is influenced by antigen engagement, environmental factors, genetics, and epigenetics.
- Low sIgM correlates with anergy and indolent CLL, while high sIgM is linked to proliferation and aggressive disease.
Conclusions:
- Variable sIgM levels significantly impact CLL behavior, influencing disease aggressiveness.
- sIgM expression levels may affect the efficacy of BCR-targeted therapies like BTK inhibitors, potentially contributing to resistance.
- Further research into BCR signaling modulation could offer new therapeutic strategies for CLL.
Abstract:
The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance.
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