Targeting the B cell receptor pathway in chronic lymphocytic leukemia

Abstract

The B cell receptor (BCR) pathway plays a crucial role in the survival, proliferation and trafficking of chronic lymphocytic leukemia (CLL) cells. Inhibitors of the key kinases in this pathway, including spleen tyrosine kinase (SYK), mammalian target of rapamycin (mTOR), phosphoinositide 3'-kinase (PI3K) and Bruton's tyrosine kinase (BTK), have been found in preclinical models to decrease CLL cell viability both directly and indirectly through modulation of the microenvironment. Recently, oral agents targeting each of these kinases have been explored in early phase clinical trials in patients with CLL. BCR pathway antagonists appear to be highly active in relapsed/refractory CLL, independent of high-risk disease markers such as del(17p). These agents have shown a unique pattern of inducing early transient lymphocytosis, which typically is associated with nodal response. Here, we review the biology of the BCR, the kinases within this pathway and their interaction with the CLL microenvironment. We also discuss data from recent and ongoing clinical trials of BCR antagonists. We address the development of potential biomarkers for response to these agents such as ZAP-70, IGHV status and CCL3, and discuss where these exciting new drugs may fit in the evolving landscape of CLL therapy.

Figure 1

The B cell receptor (BCR) signaling pathway and molecular interactions in the CLL microenvironment. Upon engagement with antigen (and independent of antigen in some cases), the BCR activates LYN and SYK kinases, which stimulate several downstream mediators. BTK activation leads to a variety of downstream effects that eventually regulate key transcription factors for B cell survival and proliferation. PI3K stimulation leads to activation of mTOR and AKT. mTOR promotes cell cycle progression from G1 to S and activates important pro-survival transcription factors. AKT has an anti-apoptotic effect, the mechanism of which remains incompletely defined. The microenvironment promotes CLL survival in a variety of complex ways. CLL cells can produce chemokines such as CCL3 and CCL4, which recruit immune cells such as T cells, which exert pro-survival signals through CD40/CD40L interactions. Nurse-like cells (NLC) have anti-apoptotic effects on the CLL cell through a variety of mediators, including APRIL, BAFF, and CD31, the latter of which interacts with CD38 and ZAP-70 to drive CLL cell proliferation. Bone marrow stromal cells (BMSC) contribute to CLL survival both through direct cell-cell contact and by producing soluble factors. Ligands such as VCAM-1 and fibronectin (FN) on the BMSC cell surface interact directly with integrins such as CD49d (VLA-4) on the CLL cell. BMSCs also produce chemokines such as CXCL12, which recruit CLL cells into the microenvironment through interactions with receptors on the CLL cell such as CXCR4.