News

Article

Molecular Mapping of CLL and Richter Syndrome Offers Crucial Insights

Author(s):

This new analysis provides an optimistic outlook on the future of chronic lymphocytic leukemia (CLL) treatment and discoveries into the background behind CLL transformation into Richter syndrome.

A molecular map of chronic lymphocytic leukemia (CLL) and Richter’s syndrome (RS) developed by examining the clonal expansion of B cells in large cohorts of patients can yield important insights into the etymology of these diseases, clonal evolution, and initiatives to improve patient care, according to a study published in Seminars in Hematology.

The clonal expansion of B cells provides a natural model of cancer evolution. CLL is the most common leukemia in economically developed countries, while RS remains associated with a poor survival prognosis, indicating the need to further understand the evolutionary processes that drive transformation of CLL to RS, the investigators wrote.

Beginning with a discussion of the CLL genome, the investigators noted that fluorescence in situ hybridization has allowed for the detection of chromosomal aberrations in both dividing cells and interphase nuclei. This is especially salient since 80% of CLL cases demonstrate a chromosomal aberration.

The invention of high-throughput sequencing (HTS), such as whole-genome sequencing (WGS), has allowed for multiple innovations, including unbiased mutation detection, mutational signature extraction, and the identification of clinically relevant biomarkers, the investigators wrote. WGS also allows for the detection of recurrent variants outside of noncoding mutations, in addition to larger variants such as copy number alterations and structural variants, according to the investigators. Beyond mutation biomarkers that were described as TP53 aberrations, HTS could possibly identify biomarkers that are prognostic in CLL.

Through the application of single-cell technologies, a higher-resolution phylogenetic map can be detected. This differs from bulk tumor sequencing, which can order somatic mutations and infer clonal dynamics, the investigators discussed. It can also further the understanding of cancer cell heterogeneity and therapeutic resistance through the profiling of genomic, transcriptomic, and other -omic modalities.

Furthermore, single-cell technologies can assess the clonal trajectories of cancer cells over time and see how they respond to therapy, the investigators noted. Numerous studies have analyzed the impact of specific therapies on CLL response, with promising results.

Besides confirming the status of cancer genes, functional studies can offer the chance to directly study the biological consequences of mutations in cancer cells. Analyses have highlighted the dysfunction of inflammatory signaling, DNA damage, and RNA regulation as consequences of mutations in CLL, the investigators found.

Molecular mapping | Image Credit: JR-50 - stock.adobe.com

Molecular mapping | Image Credit: JR-50 - stock.adobe.com

Moving to a discussion surrounding RS, they noted that recent studies have yielded several insights into the evolutionary history of CLL becoming RS. The investigators determined that most cases of RS are clonally related to antecedent CLL and distinct from diffuse large B-cell lymphoma, and that transformation to RS is associated with an increase in genomic complexity. In addition, the identification of coding mutations has allowed studies to expand the driver genes and pathways involved in mutations.

The investigators noted a pressing and essential need to use recent molecular insights involving RS to improve patient outcomes, given the disease’s short median overall survival.

Immunogenetic and transcriptomic features of RS found in 5 of 9 patients with CLL with available samples were analyzed by the investigators. In addition to raising concerns regarding the prevalence of RS subclones in patients with CLL, these finding give preliminary evidence that early RS detection can be achieved in some patients.

Despite the success of this analysis, the investigators noted that their work is incomplete and that a full understanding of RS mutations remains elusive.

“Through functional studies of mutations and the application of single-cell genomic, transcriptomic, epigenomic, and spatial data across tissues, disease states, and clinical contexts, these questions can be addressed with the promise of generating translatable knowledge to improve patient outcomes,” the investigators concluded.

Reference

Sud A, Parry EM, Wu C. The molecular map of CLL and Richter’s syndrome. Semin Hematol. Published online January 23, 2024. doi:10.1053/j.seminhematol.2024.01.009

Related Videos
1 KOL is featured in this series.
5 KOLs are featured in this series.
5 KOLs are featured in this series.
Parth Rali, MD
1 KOL is featured in this series.
4 KOLs are featured in this series
Related Content
AJMC Managed Markets Network Logo
CH LogoCenter for Biosimilars Logo