ArticleLeukemia2023
Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation.
Article in Leukemia, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- The CD40-CD154 axis in transplantation: from immunobiology to therapeutic targeting.Frontiers in immunology · 2026Review
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies.Cell death & disease · 2025Review
- Double Strike in Chronic Lymphocytic Leukemia-The Combination of BTK and BCL2 Inhibitors in Actual and Future Clinical Practice.International journal of molecular sciences · 2025Review
- Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia.Oncology reviews · 2025Review
- Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice.Blood neoplasia · 2024Article
- Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia.Leukemia · 2024Article
- NK Cells in the Lymph Nodes and Their Role in Anti-Tumour Immunity.Biomedicines · 2024Review
- Treatment of Double-Refractory Chronic Lymphocytic Leukemia-An Unmet Clinical Need.International journal of molecular sciences · 2024Review
- Electron transport chain and mTOR inhibition synergistically decrease CD40 signaling and counteract venetoclax resistance in chronic lymphocytic leukemia.Haematologica · 2024Article
- Article
Corrections and comments
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Authors and funding
11 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.