Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal B cells in peripheral blood, bone marrow, spleen, and lymph nodes. The trafficking, survival, and proliferation of CLL cells is tightly regulated by the surrounding tissue microenvironment and is mediated by antigenic stimulation, close interaction with various accessory cells and exposure to different cytokines, chemokines, and extracellular matrix components. In the last decade there have been major advances in the understanding of the reciprocal interactions between CLL cells and the various microenvironmental compartments. This article discusses the role of the microenvironment in the context of efforts to develop novel therapeutics that target the biology of CLL.

Figure 1

The CLL microenvironmental signalosome: the convergence of microenvironmental-induced signaling responses into biochemical pathways within CLL cells. Microenvironmental elements ( ) including cells (e.g. T-cells, nurse-like cells), the extracellular matrix (ECM) and enzymes (e.g. MMP9) stimulate CLL cells either directly (arrows) or via mediators such as cytokines and chemokines (dashed arrows). These extracellular triggers converge into an array of intracellular biochemical responses ( ), resulting in the up-regulation of MYC and anti-apoptotic proteins ( ), as well as additional cellular responses.

Figure 2

The B-cell receptor – a signaling complex that delivers microenvironmental-derived information into the CLL cell. The sIgM serves as the backbone of the BCR, and is associated with other transmembrane molecules (e.g. CD19, CD21). The transmembrane components of the BCR associate with a variety of enzymes (e.g. SYK, BTK) and scaffold proteins (e.g. BLNK) to form a signaling complex. This complex translates extracellular cues, predominantly antigenic stimulation, into CLL cellular responses including survival, proliferation, adhesion and migration (arrow). Tonic or cell-autonomous activation (dashed arrow) does not require extracellular stimuli.

Figure 3

Therapeutic targeting of microenvironmental-induced signaling in CLL. Current and experimental CLL therapeutics (arrows) target the various components of the microenvironment-CLL milieu and its associated signaling network. Thus the BCR and its associated components are targeted by antibodies (anti-CD19) or small molecules (e.g. SYK (e.g. fostamatinib) or BTK inhibitors (e.g. ibrutinib)). Small molecules are also utilized to inhibit mTOR, Akt, PI3K(δ) and the MAPK cascades. Extracellular inhibitors such as plerixafor or atacicept can block the association of SDF-1 or BAFF/APRIL, respectively, with their receptors on the CLL cell. Both the microenviroment (e.g. the immune system) and the outcome of its signaling responses in the CLL cells (e.g. upregulation of BCL-2) are avenues for therapeutic targeting.