Researchers at the University of Eastern Finland and their international collaborators have identified key developmental and molecular differences between the two main subtypes of chronic lymphocytic leukemia, CLL. The findings, published in PLOS ONE, show that mutated and unmutated forms of CLL may originate from distinct stages of B cell development, offering new insight into disease mechanisms and biomarker discovery.
Mutated and unmutated CLL take different developmental routes
CLL, the most common leukemia in adults, is characterised by disruption of peripheral immune system through the accumulation of abnormal B-lymphocytes. CLL is divided into mutated (M-CLL) and unmutated (UM-CLL) subtypes based on the mutation frequency of the immunoglobulin heavy chain variable region in B cells. UM-CLL is more aggressive and tends to have worse prognosis than M-CLL. The research team performed a meta-analysis of transcriptomic data from 116 patients and healthy donor B cells to explore the origins of these subtypes.
B cells go through different developmental stages in bone marrow and in lymphatic tissue germinal centres. They are classified into different subtypes depending on their maturation and function such as memory or plasma cells. The results revealed that M-CLL resembles germinal centre–dependent memory B cell subtype, CD27bright memory B cells, while UM-CLL reflects an earlier intermediary germinal centre stage, possibly explaining their differences in mutation levels and clinical behaviour.
New molecular biomarkers identified
The study highlights three genes – LPL, ZNF667 and ZNF667-AS1 – as promising biomarkers for more precise CLL patient stratification. These genes are involved in cholesterol regulation and epithelial–mesenchymal transition, processes that may contribute to disease progression and aggressiveness.
“Our results suggest that both CLL subtypes may trace back to germinal centre B cells but diverge at different points of development,” says Ahmed Mohamed, lead author from the University of Eastern Finland. “This helps us better understand why some patients experience more aggressive disease than others.”
“Identifying genes such as LPL and ZNF667 gives us tools for more precise molecular classification and potentially for new therapeutic strategies,” adds Dr Ola Grimsholm from the Medical University of Vienna.
Shared and distinct pathways
Additionally, in comparison to healthy B cells, both CLL subtypes showed alterations in pathways linked to neuroactive ligand–receptor signalling and cell–cell adhesion, while subtype-specific differences involved cholesterol metabolism (UM-CLL) and immune activation and platelet signalling (M-CLL). These findings strengthen the link between metabolic regulation, immune signalling and leukemia biology.
The project received fundings from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie agreement No101034307, Assar Gabrielsson foundation, Anna-Lisa and Bror Björnsson foundation, Adlerbert Research Foundation and the Royal Sciences and Arts in Gothenburg and the Austrian Science Fund (FWF), project PAT3959823.
Publication
Mohamed, A., et al. (2025). Germinal center trajectories and transcriptional signatures define CLL subtypes and their pathway regulators. PLoS One, 20(10), e0335069.
https://doi.org/10.1371/journal.pone.0335069