New Study Finds CLL Can Start From Multiple Abnormal B-Cell Clone Groups

New research shows that some people with chronic lymphocytic leukemia (CLL) have multiple small groups of abnormal B-cells that share cancer-like features. 

The findings suggest that CLL may develop from several early changes in B-cells over time, rather than from one single event. Read on to learn what this could mean for understanding and managing CLL.

Understanding the background: More than one clone group may be involved 

CLL is a slow-growing blood cancer that starts in lymphocytes, a type of white blood cell. The most common type starts in B lymphocytes, also called B-cells. In CLL, the B-cells are immature copies of one another, called clones.  

Many people diagnosed with CLL have an earlier, symptom-free phase called monoclonal B-cell lymphocytosis (MBL), in which the clones are below 5,000 cancer cells per microliter of blood. Once the cancer cells go over this number, it is labeled as CLL. 

25-30% of people with MBL and 5-10% of people with CLL have an oligoclonal immunoglobulin repertoire, meaning their total B-cell population has a limited number of B-cell clones responsible for producing antibodies rather than the typical diverse array of clone groups in healthy individuals. This suggests that CLL may arise from multiple small groups of abnormal B-cell clones rather than one. B-cell groups with CLL features, often referred to as CLL stereotypes, can also be found in healthy people.  

In a recent study presented at the 2025 European Hematology Association (EHA) Congress, researchers from Spain looked at how frequently other small groups of B-cell clones with CLL features were found. 

Understanding how these small groups of clones behave helps researchers learn how CLL may start and change over time. It also helps explain why some cases progress differently from others.

How the researchers studied CLL clones

Researchers analyzed samples from 367 people with CLL or MBL and compared them with 123 people without CLL or MBL. They used advanced lab techniques such as:

• Next-generation sequencing (NGS) to study immunoglobulin genes. These are genetic instructions for building antibodies that show B-cell behavior.
• Single-cell RNA and DNA sequencing to look closely at gene activity and mutations in individual cells.
• Whole genome sequencing to track how different clones evolve.

They focused on identifying small numbers of clones that coexist with the main CLL clone in the blood.

What they found: Small clone groups have CLL features 

After analyzing samples, the researchers saw: 

• 13.4% of CLL and MBL samples had more than one expanded clone group, with 75.5% of these having similar mutations.
• Small CLL clone groups made up 0.05% of all B-cells and had CLL genetic markers such as deletion of chromosomes 13q and 11q and mutations in the TP53 gene.
• In clonotypes that hadn’t expanded yet, CLL/MBL samples were 18 times more likely to have various clonotypes with almost identical CLL characteristics than non-CLL/MBL samples. 

These findings suggest that various small groups of CLL clones may already be on a path toward developing cancer-like traits. 

Why this matters: CLL may develop from early and ongoing changes

The study’s most important insight is that CLL may not arise from a single mutated cell. Instead, multiple abnormal B-cell clone groups may appear over time. These clones can share similar cancer traits and grow at different rates. In some cases, they even develop similar genetic changes separately, a process known as convergent evolution.

This means CLL could be the result of long-term processes in the immune system that start early in life, rather than a one-time event. Understanding this may help guide future strategies for monitoring early signs of CLL and personalizing treatment. 

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Source: 

• MINOR INDEPENDENT CLONES IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA HAVE A CLL-BIASED BIOLOGICAL SIGNATURE: IMPLICATIONS FOR DISEASE ONTOGENY AND EVOLUTION