PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL)

Abstract

B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use.

Fig. 1

Activation of PI3K in B cells. PI3Kδ is a central integrator of signals from the BCR, CD19, CXCR4, CXCR5, and BAFF in B cells. The precise mechanisms linking chemokine and FAFF receptors to PI3K signaling have yet to be fully elucidated. PI3K signaling is antagonized by PTEN and by SHIP which associates with the negative regulator FcγRIIB. PIP₃ and its metabolite PI(3,4)P₂ can both activate Akt and its downstream effector, including the inactivation of FOXO. By contrast, BTK can only bind PIP₃. Not shown in this figure is the complex cross regulation between PI3K and mTOR which is described in the main text and elsewhere

Fig. 2

Cellular and molecular interactions between CLL cells and the tissue microenvironment. B cell receptor (BCR) signaling is a key pathway for promoting survival and growth of CLL B cells, mediated via upstream kinases SYK and PI3Kδ, and further downstream signaling detailed in Fig. 1. In addition, interactions between CLL cells and T cells are central for the expansion of the malignant CLL clone. Interactions via CD40, expressed on the CLL cells, and CD40 ligand (CD154), as well as cytokines (IL4, TNFα, IFNγ, CCL3, CCL4), play an important role in CLL-T-cell cross talk. CLL cells are attracted and retained in tissue microenvironments, such as the secondary lymphatic tissues and the bone marrow, by chemokines that are constitutively secreted by tissue mesenchymal stromal cells (MSC) and monocyte-derived nurselike cells (NLC). These stromal cells establish chemokine gradients, such as CXCL12 and CXCL13 gradients that attract CLL cells via the corresponding G-protein-coupled chemokine receptors, CXCR4 and CXCR5, respectively. Adhesion molecules on the CLL cells, such as CD49d (VLA-4), cooperate with chemokine receptors during this process. NLC also express BAFF and APRIL, as well as CD31 for activation of respective ligands on the leukemia cells, promoting growth and survival of the CLL cells