{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:37:28Z","timestamp":1790505448519,"version":"4.1.0"},"reference-count":80,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,5,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4\/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a\/b\/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor\u2013associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-\u03baB (NF-\u03baB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40\u2013NF-\u03baB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling\/T-cell interactions in a CLL microenvironment and described a novel miR-29\u2013TRAF4\u2013CD40 signaling axis modulated by BCR activity.<\/jats:p>","DOI":"10.1182\/blood.2020005627","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T10:06:24Z","timestamp":1617012384000},"page":"2481-2494","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":59,"title":["<i>miR-29<\/i>\n                    modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors"],"prefix":"10.1182","volume":"137","author":[{"given":"Sonali","family":"Sharma","sequence":"first","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, Brno, Czech Republic;"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;"},{"name":"Faculty of Science, Masaryk University, Brno, Czech Republic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Mladonicka","family":"Pavlasova","sequence":"additional","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, Brno, Czech Republic;"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaclav","family":"Seda","sequence":"additional","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, Brno, Czech Republic;"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina Amruz","family":"Cerna","sequence":"additional","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, Brno, Czech Republic;"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Vojackova","sequence":"additional","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, Brno, Czech Republic;"},{"name":"Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;"},{"name":"Faculty of Science, Masaryk University, Brno, Czech Republic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Filip","sequence":"additional","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, Brno, Czech 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