Signaling Pathways Activated by the B-Cell Receptor in Chronic Lymphocytic Leukemia

Maria Teresa Scupoli; Giovanni Pizzolo


Expert Rev Hematol. 2012;5(3):341-348. 

In This Article

Abstract and Introduction


Over the past decade, several features of the B-cell receptor (BCR) complex have emerged as major markers for prognostic classification of B-cell chronic lymphocytic leukemia (B-CLL). In particular, the absence of somatic mutations within the immunoglobulin variable heavy chain genes (IGHV), the presence of ZAP-70 and a higher ability of the BCR to translate signals within the cell have been associated with an aggressive clinical course. Indeed, the stratification of patients with B-CLL based on BCR features suggests that heterogeneity of B-CLL clinical courses may reflect BCR signaling differences that have arisen during the evolution of leukemia. Therefore, characterizing BCR signaling profiles may help to identify signaling markers useful for patient stratification, disease monitoring and therapeutic targeting in B-CLL.


B-cell chronic lymphocytic leukemia (B-CLL) is the most common form of adult leukemia in Western countries.[1] It is characterized by the accumulation of mature, monoclonal B cells in the blood, bone marrow and lymphoid tissues. The disease mainly affects elderly individuals and, although treatable, is generally considered incurable. Patients with B-CLL exhibit a variable clinical course, with some patients having an indolent disease course and others experiencing rapid progression, treatment resistance and death.[1] Several biological parameters have been shown to be associated with clinical outcome in patients with B-CLL and help to stratify patients into risk groups. They include the presence or absence of a significant level of somatic mutations within the immunoglobulin variable heavy chain genes (IGHV),[2,3] certain chromosomal abnormalities,[4] the presence or absence of the ZAP-70 tyrosine kinase in the cytosol, and the expression of low or high levels of the CD38 surface antigen.[3,5]

Several lines of evidence suggest that stimuli from microenvironment have a key role in the onset and progression of B-CLL,[6] and it could be hypothesized that clinical heterogeneity observed in B-CLL could reflect differences in the manner that leukemic cells interpret and respond to microenvironmental cues. Among the external factors involved in B-CLL pathogenesis, antigenic stimulation mediated by the B-cell receptor (BCR) has been suggested to have a prominent role.[7,8]

Herein we discuss the role of BCR in the physiopathology of B-CLL and describe new therapeutic opportunities to target BCR signaling.


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