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miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors.

Authors
  • Sharma, Sonali1, 2, 3
  • Pavlasova, Gabriela Mladonicka1, 2
  • Seda, Vaclav1, 2
  • Cerna, Katerina Amruz1, 2
  • Vojackova, Eva1, 2, 3
  • Filip, Daniel1, 2
  • Ondrisova, Laura1, 2
  • Sandova, Veronika1, 2
  • Kostalova, Lenka1, 2
  • Zeni, Pedro F1, 2, 3
  • Borsky, Marek2
  • Oppelt, Jan1
  • Liskova, Kvetoslava4
  • Kren, Leos4
  • Janikova, Andrea2
  • Pospisilova, Sarka2
  • Fernandes, Stacey M5
  • Shehata, Medhat6
  • Rassenti, Laura Z7
  • Jaeger, Ulrich6
  • And 6 more
  • 1 Central European Institute of Technology, Masaryk University, Brno, Czech Republic. , (Czechia)
  • 2 Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic. , (Czechia)
  • 3 Faculty of Science, Masaryk University, Brno, Czech Republic. , (Czechia)
  • 4 Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic. , (Czechia)
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • 6 Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; and. , (Austria)
  • 7 Moores Cancer Center, Department of Medicine, University of California San Diego, La Jolla, CA.
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 06, 2021
Volume
137
Issue
18
Pages
2481–2494
Identifiers
DOI: 10.1182/blood.2020005627
PMID: 33171493
Source
Medline
Language
English
License
Unknown

Abstract

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-associated 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-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB 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-TRAF4-CD40 signaling axis modulated by BCR activity. © 2021 by The American Society of Hematology.

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