B-cell receptor signaling in chronic lymphocytic leukemia

Abstract

IntroductionIf we are to exploit biologic insights for new therapies of hematologic malignancies, it is important to consider 2 distinct features of the target tumor: (1) the developmental process, by which a normal cell becomes transformed into an established tumor; and (2) the susceptibility or resistance of the malignant cells to current therapies. Most investigators do not separate these 2 features, focusing only on the link between the particular aspect being studied and clinical outcome. For example, in B-cell lymphoma, gene expression profiles have been used to predict survival, an outcome more likely to be determined by susceptibility to treatment than by the pathogenic process. 1 In many cases, this restricted view is inevitable because hematologic malignancies are often treated quite quickly, making the connection between cellular features and the natural history of the tumor difficult to analyze.Among B-cell malignancies, chronic lymphocytic leukemia (CLL) is a shining exception because its relatively indolent nature enables detailed investigation of tumor cells, often in the absence of treatment, as well as observation of tumor behavior over time. This window of opportunity has facilitated the identification of prognostic factors that relate to pathogenesis. It is even possible now to detect minor clonal expansions, defined as monoclonal B-cell lymphocytoses, in ϳ 3% of healthy persons, potentially revealing the very early stages of CLL. 2 In CLL, there is the added advantage of availability of tumor cells from blood, although conclusions based on this compartment have to be tempered by the fact that critical proliferative events occur in tissue sites.There is now strong evidence that signaling via the B-cell receptor (BCR) plays a major role in the development of CLL and that it determines the variable clinical behavior. In this Perspective, we discuss the functional significance of the BCR in CLL and we describe strategies to target BCR signaling as a new therapeutic approach. Insights into pathogenesis from the expressed IgB-cell malignancies offer a major advantage to investigators, in that the immunoglobulin (Ig) component of the BCR has unique molecular features that mark the tumor cell and reveal the nature of the B cell of origin. 3 Most cases of CLL express IgM and IgD, and it is now clear that the disease can be divided into 2 main subsets, based on whether the tumor arose from a B cell before initiation of somatic hypermutation in Ig variable (V) region genes (unmutated [U] CLL) or after this process had taken place and then stopped (mutated [M] CLL). The rather dramatic difference in tumor behavior, with U-CLL being generally more aggressive than M-CLL, 4,5 was unexpected, although perhaps it should not have been, given the clinical differences between other B-cell tumor categories.In CLL, the Ig expressed at the cell surface is rarely lost, indicating an essential influence on the tumor cell. Because the IGHVHDHJ and IGLVLJ sequences, and the isotype, reflect the normal counterpart, it i...

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

“…The most recent review on BCR signaling in CLL cells supports a paradigm, whereby Lyn is responsible for mediating proximal and distal signaling events following BCR engagement on CLL cells (3). The results we present in the current study provide further insight into this paradigm.…”

“…This incurable disease is associated with considerable morbidity and mortality due to the suppression of immune function and hematopoiesis that results from expansion of CLL cells within lymphoid organs and bone marrow (2). It is widely accepted that signals generated by engagement of the B-cell receptor (BCR) play an important role in the pathogenesis of CLL (3). This is because the structure of the BCR in CLL cells from different patients can show a very high degree of similarity, indicating that antigens of a similar nature drive development of the disease (4,5).…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…BCR signaling has long been recognized as a major player in CLL development, based on structural restrictions of the BCR, and BCRdependent survival and growth of the malignant B cells [65][66][67][68]. As compared with normal B cells, CLL has distinct BCR-related features that include low-level IgM expression, variable response to antigen stimulation, and activation of anti-apoptotic signaling pathways [65][66][67][68][69].…”

“…As compared with normal B cells, CLL has distinct BCR-related features that include low-level IgM expression, variable response to antigen stimulation, and activation of anti-apoptotic signaling pathways [65][66][67][68][69]. Recent work suggests a ligand-independent signaling arising from such CLL BCR [70].…”

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

“…Expression of, and signaling from, the pre‐BCR or BCR is also required for the continuous growth of several B‐cell lymphomas (Gauld et al , 2002; Kuppers, 2005; Lenz & Staudt, 2010; Stevenson et al , 2011). For instance, most B cells of chronic lymphocytic leukemia (B‐CLL) carry an auto‐aggregated BCR, which promotes continuous ITAM and PI3K signaling and is required for the expansion and survival of these tumor cells (Duhren‐von Minden et al , 2012).…”