Photo Credit: Nemes Laszlo

The following is a summary of “BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia,” published in the March 2025 issue of the Molecular Cancer by Chong et al.

Current genetic biomarkers in chronic lymphocytic leukemia (CLL) provide valuable insights into patient prognosis and response to chemoimmunotherapy but are insufficient for predicting responses to targeted therapies. With the increasing approval of novel targeted agents for CLL, there is an urgent need for non-genetic biomarkers that can guide personalized treatment strategies. In this study, researchers integrated functional precision medicine techniques with multi-omics data to identify predictive biomarkers of treatment response in CLL. The study group employed BH3 profiling, a functional assay that measures cytochrome c loss to assess cellular dependence on anti-apoptotic proteins, alongside whole-exome and targeted sequencing, genome-wide DNA methylation analysis, RNA sequencing, protein profiling, and functional studies. The initial investigation of 73 patients with CLL  in a discovery cohort revealed a strong association between higher BCL-2 dependence and the presence of favorable genetic biomarkers. 

Moreover, BCL-2 dependence correlated with distinct gene expression patterns and signaling pathways indicative of enhanced sensitivity to targeted therapies. Functional validation in CLL cell lines and additional patient samples confirmed the causality of these associations. To further substantiate the findings, they analyzed primary CLL cells from an independent cohort of 54 patients enrolled in a prospective phase 2 clinical trial evaluating the combination of the BTK inhibitor ibrutinib with chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab). In this validation cohort, elevated BCL-2 dependence was a strong predictor of favorable clinical responses, independent of the genetic background of the CLL cells. Their findings establish BCL-2 dependence as a robust, functional biomarker for predicting treatment response in CLL, highlighting the importance of apoptotic signaling in therapeutic stratification. 

By integrating functional profiling with genomic and molecular analyses, this approach offers a novel strategy for optimizing targeted therapy combinations and advancing personalized treatment in CLL.

Source: molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02260-7