Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia

• Published in: Scientific reports 2021-03, Vol.11 (1), p.5127-10, Article 5127
• Main Authors: Cui, Xue Yan, Tjønnfjord, Geir Erland, Kanse, Sandip M., Dahm, Anders Erik Astrup, Iversen, Nina, Myklebust, Christiane Filion, Sun, Ling, Jiang, Zhong Xing, Ueland, Thor, Campbell, James J., Ho, Mitchell, Sandset, Per Morten
• Format: Article
• Language: English
• Subjects: 692/499; 692/53; Adult; Aged; Aged, 80 and over; beta Catenin - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell surface; Chemokine CXCL12 - genetics; Chronic lymphocytic leukemia; CXCL12 protein; CXCR4 protein; Enzyme-linked immunosorbent assay; Female; Gene Expression Regulation, Leukemic - genetics; Glypicans - genetics; Hematopoietic stem cells; Heparan sulfate proteoglycans; Homing behavior; Humanities and Social Sciences; Humans; Immunofluorescence; Immunoprecipitation; Infiltration; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - blood; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lipoproteins - blood; Lymphatic leukemia; Male; Middle Aged; multidisciplinary; Polymerase chain reaction; Proteinase inhibitors; Receptors, CXCR - genetics; Receptors, CXCR4 - genetics; Science; Science (multidisciplinary); Serine; Serine proteinase; Signal Transduction - genetics; Stem cells; Tissue factor; Western blotting; Wnt protein; β-Catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84695-8

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.