The microenvironment in hairy cell leukemia: pathways and potential therapeutic targets

Abstract

Hairy cell leukemia (HCL) cells accumulate and proliferate in the spleen and the bone marrow. In these tissue compartments, HCL cells interact with accessory cells, matrix proteins, and various cyctokines, collectively referred to as the 'microenvironment.' Surface receptors expressed on HCL cells and respective stromal ligands are critical for this cross-talk between HCL cells and the microenvironment. Chemokine receptors, adhesion molecules (integrins, CD44), the B cell antigen receptor (BCR), and CD40, expressed on the HCL cells, are likely to be critical for homing, retention, survival, and expansion of the neoplastic B cells. Some of these pathways are now targeted in first clinical trials in other mature B-cell malignancies. We summarize key aspects of the cellular and molecular interactions between HCL cells and their microenvironment. Also, we outline future prospects for therapeutic targeting of the microenvironment in HCL, focusing on CXCR4 and kinase inhibitors (Syk, Btk, phosphatidylinositol 3-kinase [PI3K]) that target B cell receptor signaling.

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.

Figure 2

Cellular and molecular interactions between HCL cells and their microenvironment. HCL cells express CXCR4 chemokine 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 κB (NFκB) pathway.