Categorizing Distinct Pathogenic Processes in Chronic Lymphocytic Leukemia With Multiomics

An international team led by researchers at the University Hospital of Ulm has now comprehensively profiled and categorized over 700 tumor samples from patients with chronic lymphocytic leukemia (CLL) by analyzing multiple levels of encoded biologic information.

Through detailed mapping of the derived information, they identified major biologic categories associated with distinct modes of resistance to different treatment combinations.

Besides changes indicating heterogeneous levels of inflammatory activity, the degree of genomic instability turned out to be a major discriminatory feature for the tumor subgroups.

The newly established tumor classifications represent a significant advance in understanding the underlying biology and mechanisms of resistance in CLL and may ultimately improve prognostic models for personalized treatment approaches, possibly translatable to other tumor entities.

As reported by the researchers in Nature Communications, tumor sample analysis included the assessment of gene mutations, chromosomal aberrations, DNA methylation, gene and protein expression, and associated pathway-signaling activity.

In cancer biology, high levels of genomic instability increase the likelihood of alterations occurring in the genome and the degree of genomic instability is largely determined by the tumors’ ability to quickly recognize and repair acquired DNA damage.

Genomic instability in CLL has been linked to mutations or chromosomal losses of regions encoding the cellular “guardians” of the genome, the so-called tumor suppressor genes. Tumors exhibiting such alterations usually have a poor outcome. Early detection can help to determine the most appropriate treatments. However, in many CLL cases genomic instability can occur without such detectable alterations.

The authors were able to decode the tumor biology and translate the underlying information in a way that makes it possible to categorize tumors irrespective of detectable losses or mutations of tumor suppressor or DNA repair genes.

The authors further discovered that genomically instable tumors do not just shut down DNA repair but they also show boosted and highly error-prone repair activity. This further increases accumulation rates of genomic alterations, accelerating the development of resistance. The findings also imply that preexisting latent genomic instability may reach critical levels during certain developmental steps of the B cell and precede the inactivation of tumor suppressor genes.     

“This observation is very interesting as it highlights the importance of multiple pathogenic elements during malignant transformation and further evolution. Exploiting the weak spots in this cascade may provide additional opportunities for early detection or therapeutic intervention,” explains Dr. Johannes Bloehdorn, from the University of Ulm, and lead author of the study.

Another major subgroup identified in this study, showing the lowest degree of genomic instability, exhibits characteristics observed during the process of metastasis in solid tumors, which were previously not known to build subgroup-specific functional networks in CLL.

CLL cells can reach any part of the body via the bloodstream. Therefore, it appears redundant to develop mechanisms that enable the cell to break free from a tumor to search for a new niche for better survival, which is represented through the process of metastasis in solid tumors. These uncovered networks may increase the ability for the leukemia cells to exit the bloodstream and migrate to certain tissues to “take a rest”.

“Several new targeted treatment approaches exactly address related mechanisms and the cells ability to migrate to or stay in lymphoid organs. When forced out of this pro-survival niche, cells slowly “starve” since being cut-off their lifeline,” says Dr. Bloehdorn.

However, in contrast to the genomically instable subgroup, these CLL cells show a very high dependency on genomic integrity to retain full functionality of their signaling networks. Even after intensive chemotherapy (which aims to disrupt DNA integrity to kill the tumor cell), cases of this subgroup were clearly traceable through the specific gene expression signatures, which were used as an “identity code”. These cases maintained the lowest frequency of critical chromosomal aberrations and gene mutations, which occur at higher frequency after chemotherapy.

“It appears to be elementary for tumor cells of this subgroup to be locked into a state where they can avert occurrence of DNA-damage and activation of associated repair-pathways. This finding also provides new perspectives on how treatment resistance can develop in CLL as the discovered subgroups point to highly different trajectories,” notes Dr. Bloehdorn.

Future efforts will now focus on the mechanisms during early tumorigenesis, which promote genomic instability. This will help to better explain the underlying pathogenic processes and categorize tumors in an early stage. 

Reference: Bloehdorn J, Braun A, Taylor-Weiner A, et al. Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia. Nat Commun. 2021;12(1):5395. doi: 10.1038/s41467-021-25403-y