{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T09:00:35Z","timestamp":1793523635900,"version":"4.5.0"},"reference-count":60,"publisher":"American Society of Hematology","issue":"22","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor\u2013targeted 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\u2013DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P &amp;lt; .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, \u03b22-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 &amp;lt; .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node\u2013derived 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 &amp;lt; .001) that was mediated by p65 NF-\u03baB 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-2R\u03b3null mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton\u2019s 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.<\/jats:p>","DOI":"10.1182\/blood.2020005964","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T20:32:09Z","timestamp":1610569929000},"page":"3064-3078","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":37,"title":["TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target"],"prefix":"10.1182","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6469-1109","authenticated-orcid":false,"given":"Emma","family":"Kennedy","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Falmer, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8443-9595","authenticated-orcid":false,"given":"Eve","family":"Coulter","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;"},{"name":"Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Halliwell","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8923-6025","authenticated-orcid":false,"given":"Nuria","family":"Profitos-Peleja","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Walsby","sequence":"additional","affiliation":[{"name":"Cardiff CLL Research Group, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5394-1889","authenticated-orcid":false,"given":"Barnaby","family":"Clark","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, King\u2019s College Hospital, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth H.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom;"},{"name":"Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-1534","authenticated-orcid":false,"given":"Thomas A.","family":"Burley","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Falmer, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-1157","authenticated-orcid":false,"given":"Simon","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Falmer, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8046-0386","authenticated-orcid":false,"given":"Stephen","family":"Devereux","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Fegan","sequence":"additional","affiliation":[{"name":"Cardiff CLL Research Group, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-1157","authenticated-orcid":false,"given":"Christopher I.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Primary Care and Public Health, Brighton and Sussex Medical School, Falmer, United 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Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Seiffert","sequence":"additional","affiliation":[{"name":"German Cancer Research Centre (DKFZ), Heidelberg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9529-2111","authenticated-orcid":false,"given":"Angelo","family":"Agathanggelou","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7815-8970","authenticated-orcid":false,"given":"Ceri","family":"Oldreive","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; 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