B Cell Chronic Lymphocytic Leukemia: Lessons Learned from Studies of the B Cell Antigen Receptor

Abstract

B cell chronic lymphocytic leukemia (B-CLL) is an accumulative disease of slowly proliferating CD5(+) B lymphocytes that develops in the aging population. Whereas some patients with B-CLL have an indolent course and die after many years from unrelated causes, others progress very rapidly and succumb within a few years from this currently incurable leukemia. Over the past decade studies of the structure and function of the B cell antigen receptor (BCR) used by these leukemic cells have helped redefine the nature of this disease. In this review we summarize and reinterpret several aspects of these BCR-related studies and how they might relate to the disease. In particular, we address the ability of antigens to select out and drive B cell clones from the normal state to overt leukemic cells by binding to BCRs that are relatively unique and characteristic of B-CLL cells. The differential capacity of some B-CLL cases to continue to transduce signals through the BCR during the leukemic phase and the consequences for the in vivo biology of the leukemic clone is also considered. Finally, we discuss current and emerging views of the cellular origin of B-CLL cells and the differentiation pathways down which we believe these cells progress.

Igβ(CD79b) mRNA expression in chronic lymphocytic leukaemia cells correlates with immunoglobulin heavy chain gene mutational status but does not serve as an independent predictor of clinical severity

“…Thus, the finding that patients in the group with unmutated IgV H genes have a higher mean Igb mRNA level in their malignant B-cell clone would be consistent with the correlation with an ''activated'' gene expression profile (reviewed in Ref. 54).…”

Correlation between ZAP‐70, phospho‐ZAP‐70, and phospho‐Syk expression in leukemic cells from patients with CLL

“…The possibility that ongoing signaling is involved in achieving an improved prognosis differs from the concept previously proposed by others that antigen receptor signaling enhances cell survival and portends a worse prognosis (1,2,30,31). It has recently been suggested that Syk inhibition may represent a valuable therapeutic option for CLL patients (30,31).…”

“…Patients display a variable clinical course with a significant proportion demonstrating a poor prognosis and the remainder following an indolent disease progression. Significant associations between B cell antigen receptor signaling and clinical course have been observed (1,2). Most saliently, high levels of expression of ZAP-70 have been shown to correlate with a poor prognosis although the mechanism has not been elucidated (3).…”

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

“…The response of CLL cells to the microenvironment is heterogeneous, and cells originating from more aggressive subtypes of CLL (e.g., IgVH unmutated, ZAP70 + , and CD38 + ) tend to respond more robustly to external signals (3)(4)(5). In particular, an antigenic stimulation is considered to play a central role in the evolution and progression of CLL (6). Antigenic stimulation is channeled into the cytoplasm of CLL via the BCR, which is a multimolecular complex comprised of surface IgM and associated components within the membrane plane, including CD19, CD21 and CD81, and associated cytoplasmic accessory/signaling molecules, including Syk, and in some patients ZAP70 (3,6,7).…”

“…In particular, an antigenic stimulation is considered to play a central role in the evolution and progression of CLL (6). Antigenic stimulation is channeled into the cytoplasm of CLL via the BCR, which is a multimolecular complex comprised of surface IgM and associated components within the membrane plane, including CD19, CD21 and CD81, and associated cytoplasmic accessory/signaling molecules, including Syk, and in some patients ZAP70 (3,6,7). Owing to the prime importance of the BCR in the physiology of malignant B cells, the expression of some of its components and associated molecules serves as prognostic factors (e.g., ZAP70) (8) or as therapeutic targets (e.g., CD20, Syk, Btk) in CLL and other lymphoproliferative disorders (LPD) (9,10).…”