title: Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis.
abstract: Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) upregulate CD20 on CLL cells and that administering ibrutinib downmodulates CD20 (MS4A1) expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4(dim)CD5(bright) subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4(bright)CD5(dim) cells). We found that CD20 is directly upregulated by CXCR4 ligand stromal cell-derived factor 1 (SDF-1α, CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4-inhibitor plerixafor block SDF-1α-mediated CD20 upregulation. Ibrutinib also downmodulated Mcl1 levels in CLL cells in vivo and in coculture with stromal cells. Overall, our study provides a first detailed mechanistic explanation of CD20 expression regulation in the context of chemokine signaling and microenvironmental interactions, which may have important implications for microenvironment-targeting therapies.
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pavlasova
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Marek
authors.initials: M
authors.lastname: Borsky
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Vaclav
authors.initials: V
authors.lastname: Seda
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Katerina
authors.initials: K
authors.lastname: Cerna
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Jitka
authors.initials: J
authors.lastname: Osickova
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy;
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Martin
authors.initials: M
authors.lastname: Trbusek
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Moores Cancer Center, Department of Medicine, University of California San Diego, La Jolla, CA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic;
authors.forename: Marek
authors.initials: M
authors.lastname: Mraz
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D018951:Antigens, CD20 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D018951:Antigens, CD20; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D019718:Receptors, CXCR4; C551803:ibrutinib; D000225:Adenine