ArticleBlood2021
TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target.
Article in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 25 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
25 citing papers in PubMed, 30 citations in OpenAlex.
- STAT3 as a Candidate Shared Regulator of the CXCR4/CXCL12 and CXCR5/CXCL13 Homing Axes in Chronic Lymphocytic Leukemia.International journal of molecular sciences · 2026Review
- NIBAN2/FLII/RREB1 Axis Drives Glioma Stem Cell Malignancy via TLR3 Pathway Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Toll-like receptors: versatile players in tumor.Frontiers in immunology · 2026Review
- Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming.International journal of molecular sciences · 2025Review
- PD-1 expression identifies proliferating malignant CLL B cells and is a potential biomarker of response to BTK inhibitor therapy.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unleashing the TLR9-driven multilineage differentiation of myeloid leukemia cellsMolecular therapy. Nucleic acids · 2025Article
- MYC target gene activation in chronic lymphocytic leukemia and richter transformation: links to aggressiveness and tumor microenvironment interactions.Frontiers in pharmacology · 2025Article
- TLR9: A Double-Dealing Toll-Like Receptor.ImmunoTargets and therapy · 2025Review
- Exploring the prognostic value of T follicular helper cell levels in chronic lymphocytic leukemia.Scientific reports · 2024Article
- Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death.Cell death & disease · 2024Article
- Electron transport chain and mTOR inhibition synergistically decrease CD40 signaling and counteract venetoclax resistance in chronic lymphocytic leukemia.Haematologica · 2024Article
- Toll-like receptor 9 signaling in chronic lymphocytic leukemia cell lines.FEBS open bio · 2023Article
- Article
- In Vitro 3D Spheroid Culture System Displays Sustained T Cell-dependent CLL Proliferation and Survival.HemaSphere · 2023Article
- Article
- Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation.Leukemia · 2023Article
- NF-kB and the CLL microenvironment.Frontiers in oncology · 2023Review
- NF-κB fingerprinting reveals heterogeneous NF-κB composition in diffuse large B-cell lymphoma.Frontiers in oncology · 2023Article
- Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives.Frontiers in immunology · 2023Review
- Old and New Facts and Speculations on the Role of the B Cell Receptor in the Origin of Chronic Lymphocytic Leukemia.International journal of molecular sciences · 2022Review
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
23 authors at 10 institutions in 3 countries.
Funding
Abstract
Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide-DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P < .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, β2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P < .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node-derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P < .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.
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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 OpenQuestion graph.