ArticleMolecular cancer2025
BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Acalabrutinib Versus Venetoclax Plus Obinutuzumab in Treatment-Naive Chronic Lymphocytic Leukemia: A Real-World Propensity Score-Matched Study.Cancer medicine · 2026Article
- When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2026Review
- BCL-2 and BCL-xL in Cancer: Regulation, Function, and Therapeutic Targeting.International journal of molecular sciences · 2026Review
- CD47 blockade-driven necroptosis complements BCL-2 inhibition-driven apoptosis in lymphoid malignancies.Journal of hematology & oncology · 2026Article
- Development and Validation of Prognostic Models for Treatment Response of Patients with B-Cell Lymphoma: Standard Statistical and Machine-Learning Approaches.Journal of clinical medicine · 2025Article
- Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.Leukemia · 2025Article
- Acute myeloid leukemia drug resistance: targetable nodes and the clinical trajectory of small-molecule inhibitors.Frontiers in pharmacology · 2025Review
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17 authors.
Funding
Abstract
backgroundEstablished genetic biomarkers in chronic lymphocytic leukemia (CLL) have been useful in predicting response to chemoimmunotherapy but are less predictive of response to targeted therapies. With several such targeted therapies now approved for CLL, identifying novel, non-genetic predictive biomarkers of response may help to select the optimal therapy for individual patients.
methodsWe coupled data from a functional precision medicine technique called BH3-profiling, which assesses cellular cytochrome c loss levels as indicators for survival dependence on anti-apoptotic proteins, with multi-omics data consisting of targeted and whole-exome sequencing, genome-wide DNA methylation profiles, RNA-sequencing, protein and functional analyses, to identify biomarkers for treatment response in CLL patients.
resultsWe initially studied 73 CLL patients from a discovery cohort. We found that greater dependence on the anti-apoptotic BCL-2 protein was associated with prognostically favorable genetic biomarkers. Furthermore, BCL-2 dependence was strongly associated with gene expression patterns and signaling pathways that suggest a more targeted drug-sensitive milieu and was predictive of drug responses. We subsequently demonstrated that these associations were causal in cell lines and additional CLL patient samples. To validate the findings from our discovery cohort and in vitro studies, we utilized primary CLL cells from 54 additional patients treated on a prospective, phase-2 clinical trial of the BTK inhibitor ibrutinib given in combination with chemoimmunotherapy (fludarabine, cyclophosphamide, rituximab) and confirmed in this independent dataset that higher BCL-2 dependence predicted favorable clinical response, independent of the genetic background of the CLL cells.
conclusionWe comprehensively defined BCL-2 dependence as a potential functional and predictive biomarker of treatment response in CLL, underscoring the importance of characterizing apoptotic signaling in CLL to stratify patients beyond genetic markers and identifying novel combinations to exploit BCL-2 dependence therapeutically. Our approach has the potential to help optimize targeted therapy combinations for CLL patients.
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