Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.
Highlights
Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia [1,2]
We found that the CLL B-cell receptor for antigen (BCR) named "Ig014", which belonged to the stereotyped subset 1, recognized a range of proteins sized between 45 and 57 kDa that were expressed in the nurse-like cells (NLC) extract and the stromal cell extracts (Figure S1)
To identify the stromal proteins recognized by CLL BCR Ig014, the NLC protein extract was subjected to two-dimensional gel electrophoresis (Figure 1A)
Summary
Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia [1,2]. This incurable disease most commonly consists of malignant B-cells expressing common B-cell markers as well as monoclonal membrane immunoglobulin, the B-cell receptor for antigen (BCR) [3]. In lymphatic tissues and the bone marrow, CLL cells are in close contact with a connective tissue network of mesenchymaderived stromal cells [4,5,6] including mesenchymal marrow stromal cells [7,8], CD68+ monocyte-derived nurse-like cells (NLC)[4], and follicular dendritic cells [9]. This supportive hematopoietic microenvironment protects CLL cells from spontaneous and drug-induced apoptosis [4] and is studied as a novel drug target in CLL [6,10,11]. One major cytokine axis involves the microenvironmental expression and secretion of stromal cell-derived factor-1 (SDF-1)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
