Microenvironment in HCL 95
Figure 1. Expression of chemokine receptors and adhesion molecules on HCL cells. These overlay histograms depict fluorescence intensities of CD19/CD11c/CD103-positive, CD19- gated HCL cells, stained with monoclonal antibodies (mAbs) toward the antigens that are displayed above or below each of the histograms. The light gray histograms depict the fluorescence intensities of HCs stained with respective isotype control mAbs for comparison with the specific mAbs (dark gray). HCL cells express CXCR4, CD49d, CD44, and CD40, but are negative for CXCR3 and CXCR5.
CD106) and fibronectin (FN) on stromal and endothelial cells, and as part of the extracellular matrix [13–15] (Figure 2). aMb2 (CD11b), aXb2 (CD11c), and aEb7 (CD103) are also expressed on HCL cells and are important for immunophenotyp- ing of HCL (CD11c, CD103), but their function is less defined. The aVb3 integrin functions as a receptor for vitronectin (VN) and platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31) and is important in HC motility. CD44 is expressed on HCs and functions as a receptor for hyaluronan [16]. HCs binding to hyaluronan via CD44 enhance autocrine production of FN and fibroblast growth factor-2 (FGF-2) [17], which, along with HC- derived transforming growth factor-b1 (TGF-b1) [18] is involved in the development of the marrow fibrosis typically seen in HCL. Functionally, CXCR4 and VLA-4 are critical for
migration, adhesion, and retention of normal hema- topoietic progenitors within the marrow [19]. Neo- plastic B cells utilize these molecules to access and parasitize within protective marrow niches that normally are occupied by hematopoietic progenitors [20]. Marrow stromal cells (MSCs) constitutively express the ligands for CXCR4 and VLA-4 (CXCL12, and VCAM1 and FN, respectively; Figure 2), and contact between MSCs and malignant B cells induces cell adhesion-mediated drug resis- tance (CAM-DR), a primary drug resistance me- chanism that may account for minimal residual disease after conventional therapies. Given the high
Figure 2. Cellular and molecular interactions between HCL cells and their microenvironment. HCL cells express CXCR4 chemo- kine receptors and adhesion molecules for adhesion to MSCs, endothelial cells, and extracellular matrix. These pathways are critical for homing and retention within the marrow and possibly also the spleen. In these tissues, HCL cells can also interact with other accessory cells, such as T cells, and may become activated via the BCR. It is currently unknown whether BCR-related kinases (Syk, Btk, PI3K) play a role in BCR signaling in HCL; however, these kinases and CXCR4 are currently targeted in first clinical trials in patients with other mature B-cell malignancies. Cross-talk between HCL cells and their microenvironment leads to activation of downstream pathways in HCs, such as mitogen activated protein (MAP) kinases and the nuclear factor kB (NFkB) pathway.
affinity of HCL cells for homing and retention within the marrow, and the high expression of CXCR4 and VLA-4 integrins on HCL cells, we speculate that these molecules induce HC adhesion to MSCs and thereby retention and protection of HCs in the marrow. Ongoing functional in vitro studies will determine the relevance of CXCR4 and VLA-4 for MSC adhesion and drug resistance in HCL.
Importance of B cell antigen receptor in hairy cell leukemia microenvironment
The very raison d’e ˆtre of mature B-cells is their
antigen (Ag) receptor. It follows that in mature B-cell malignancies the concept of the microenvironment as a regulator of malignant B-cell growth is tightly linked to the possible role of Ag stimulation [21]. Chronic B cell antigen receptor (BCR) stimulation by latent microbial or auto-Ag can trigger the development and expansion of malignant B-cells. The majority of HCL cases display mutated im- munoglobulin variable region genes (M-HCL) [22] and a restricted set of BCR with immunoglobulin (Ig) heavy chain variable (V) gene sequences that are identical or stereotyped in subsets of patients [23– 27], suggesting that these BCRs bind similar antigens
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