title: Lymph node-induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin-1.
abstract: Emerging evidence indicates that the tumour microenvironment (TME) regulates the behaviour of chronic lymphocytic leukaemia (CLL). However, the precise mechanism and molecules involved in this process remain unknown. Gene expression profiles of CLL cells from lymph node (LN), bone marrow (BM) and peripheral blood (PB) indicate overexpression of a tolerogenic signature in CLL cells in lymph nodes (LN-CLL). Based on their role in B cell biology, the progression of CLL, or immune regulation, a few genes of this 83-gene signature were selected for further analyses. We observed a significant correlation between the clinical outcomes and the expression of CAV1 (P = 0·041), FGFR1 isoform 8 (P = 0·032), PTPN6 (P = 0·031) and ZWINT (P < 0·001). CAV1, a molecule involved in the regulation of tumour progression in other cancers, was seven-fold higher in LN-CLL cells compared to BM- and PB-CLL cells. Knockdown of CAV1 expression in CLL cells resulted in significantly decreased migration (P = 0·016) and proliferation (P = 0·04). When CAV1 was knocked down in B and T cell lines, we observed an inability to form immune synapses. Furthermore, CAV1 knockdown in CLL cells impaired their ability to form immune synapses with autologous T lymphocytes and allogeneic, healthy T cells. Subsequent analyses of microarray data showed differential expression of cytoskeletal genes, specifically those involved in actin polymerization. Therefore, we report a novel role for CAV1 in tumour-induced immunosuppression during the progression of CLL.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Gilling
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mittal
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Nagendra K
authors.initials: NK
authors.lastname: Chaturvedi
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aoun
authors.affiliation: Internal Medicine-Oncology/Hematology Section, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bierman
authors.affiliation: Internal Medicine-Oncology/Hematology Section, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bociek
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051242:Caveolin 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D054992:Immunological Synapses / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D009363:Neoplasm Proteins