Novel Signaling Pathway in Chronic Lymphocytic Leukemia - Pathophysiology and New Target for Therapy

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. The clinical course varies among patients with CLL: in some it is indolent and prolonged while others experience an aggressive disease with a short life expectancy. In the last decade, the B-cell receptor (BCR) has emerged as a pivotal stimulus in CLL pathogenesis. The BCR responsiveness in CLL cells is heterogeneous among patients and correlates with disease aggressiveness. Our understanding of the critical role of the BCR pathway in CLL pathogenesis made it a central therapeutic target in this disease. Small inhibitory molecules, such as ibrutinib (directed against Btk), induce dramatic clinical responses in CLL patients. These are particularly prominent within the tissue compartments, and characterized by rapid shrinkage of enlarged lymph nodes and splenomegaly, and overcome classical poor prognostic factors such as genomic aberrations in the p53 gene. We have recently identified ectopic expression of several proteins in CLL cells that are involved in the BCR signaling. Their expression levels correlate with ZAP70 expression as well as time to disease progression and treatment. Herein, we provide a novel paradigm for BCR signaling in CLL, where an alternative signaling cascade exits in addition to the classical pathway. Our data may further suggest that combined targeting of the classical and alternative BCR pathways could be a more effective approach to treat CLL, and perhaps define novel therapeutic targets within the BCR pathway, as well as novel prognostic tools in CLL. These findings may also be applicable in future research of other lymphoproliferative diseases which depend on microenvironmental interactions.