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Lymph node‐induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin‐1
Author(s) -
Gilling Christine E.,
Mittal Amit K.,
Chaturvedi Nagendra K.,
Iqbal Javeed,
Aoun Patricia,
Bierman Philip J.,
Bociek Robert G.,
Weisenburger Dennis D.,
Joshi Shantaram S.
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2012.09148.x
Subject(s) - gene knockdown , immune system , chronic lymphocytic leukemia , cancer research , lymph node , bone marrow , biology , gene signature , immunology , gene expression , leukemia , gene , biochemistry
Summary 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 CAV 1 ( P = 0·041), FGFR 1 isoform 8 ( P = 0·032), PTPN 6 ( P = 0·031) and ZWINT ( P < 0·001). CAV 1, 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 CAV 1 expression in CLL cells resulted in significantly decreased migration ( P = 0·016) and proliferation ( P = 0·04). When CAV 1 was knocked down in B and T cell lines, we observed an inability to form immune synapses. Furthermore, CAV 1 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 CAV 1 in tumour‐induced immunosuppression during the progression of CLL .