Mutations in KLHL6 Associated With Tangible Disease Characteristics in Diffuse Large B-Cell Lymphoma

Recurrent mutations in Kelch-like family member 6 (KLHL6) can alter oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL), inducing actionable, targetable disease characteristics and leading to poor outcomes in patients with the disease, according to the results of a study published in Blood Cancer Discovery.¹

Image credit: LASZLO | stock.adobe.com

Chemoimmunotherapy is curative in many patients with DLBCL, yet a third of patients relapse with poor outcomes. Precision medicine strategies in DLBCL are limited to utilizing antibodies to attack antigens of mature B-cells, antibody-drug conjugates, or chimeric antigen receptor-equipped T-cells.¹

These limited treatment options have led to a need for better molecular understanding of the oncogenic mechanisms in DLBCL. A functional characterization of the genomic drivers in the disease is essential for the development of new, rational, and personalized medicine approaches.¹

BCR conveys signals that can determine the differentiation and survival of maturing B-cells in the germinal center reaction. The germinal center regulator of B-cell maturation is KLHL6, which is recurrently mutated in DLBCL; yet a link to oncogenic BCR signaling – and how exactly KLHL6 mutations promote lymphomagenesis – has remained unknown, according to the investigators.¹

The study authors aimed to examine the molecular picture of KLHL6 in DLBCL, and through proteomic profiling and functional characterization, discover how these mutations can change the function and expression of BCR.¹

Through their translational investigation, which included comprehensive proteomic analyses of KLHL6 and its mutations, they discovered novel functionalities for the protein. Importantly, they found that Bric-a-brac Tramtrack Broad (BTB) domain mutants of KLHL6 fail to heterodimerize and promote degradation of the substrates CD79A, CD79B, and IgM, constituting the BCR complex.¹

The expression of the BTB-mutant KLHL6^L65P was observed to increase BCR surface levels on the plasma membrane, which induced a hyperresponsive phenotype to BCR signaling. Additionally, the functional anomalies exhibited by recurring BTB and Kelch domain mutants induced phenotypic changes distinguishing them from the total genomic ablation of KLHL6, according to the study authors.¹

“Together, our findings reshape the pathogenic role of KLHL6 mutations in lymphoma,” the study investigators wrote, with an anticipation that their findings could extend to other B-cell diseases with KLHL6 mutations such as chronic lymphocytic leukemia and B-cell autoimmunity.¹

One critical finding was that, in some of the patients with DLBCL enrolled in the study, the KLHL6 protein was entirely absent from their cells. Modeling showed that the loss of KLHL6 in lymphoma cells greatly increased the number of B-cell receptors. The investigators said that this could be permissive to the oncogenic chronic active mode of BCR signaling.²

“The lymphoma cases where the KLHL6 protein was absent were associated with a poor prognosis. The identification of pathogenic mechanisms relevant to these patients is particularly important for improving their prognoses through drug development,” said Sirpa Leppä, professor of oncology, who leads the research group.²

Concurrently, these findings can allow future treatment outcomes to be improved by targeting therapies based on different cancer biomarkers, attacking proteins that can lead to dismal outcomes in patients.²

Regarding future exploration, the investigators discussed how the distinct impacts of different KLHL6 variants on BCR plasma membrane levels and signaling lead to more questions for future studies in determining what BCRs are coupled with these different mutations and what antigens they could recognize.¹

“The new findings open avenues to tailoring therapies, as the abnormal amount and activity of the B-cell receptor can be targeted pharmacologically. However, more research is still needed,” notes Leo Meriranta, MD, a doctoral researcher at the University of Helsinki.²

References

1. Meriranta L, Sorri S, Huse K, et al. Disruption of KLHL6 fuels oncogenic antigen receptor signaling in B-cell lymphoma. Blood Cancer Discov. 2024. doi:10.1158/2643-3230.BCD-23-0182

2. EurekAlert! Researchers uncover mechanism that fuels growth of aggressive B-cell lymphoma. News release. Released June 18, 2024. Accessed July 3, 2024. https://www.eurekalert.org/news-releases/1048597