BCR Signaling in B-CLL
BCR expression is maintained in most B-cell neoplasms, including B-CLL, indicating a role in the evolution of tumor cells. In order to gain insights into its pathophysiological relevance, BCR signaling has been extensively studied in B-CLL during the last decades, either in the absence or presence of external stimuli. When compared with healthy B cells, B-CLL cells exhibit higher intrinsic BCR signaling activity (tonic BCR signaling). In particular, most B-CLL B cells show constitutive phosphorylation of SYK and NF-κB,[29–31] whereas constitutive phosphorylation of ERK is present in almost half of the cases of B-CLL. It is known that tonic signaling of BCR is required by normal B cells to properly develop, be maintained and survive. The existence of tonic BCR signaling suggests that antigen-independent BCR signaling may be involved in oncogenic mechanisms in B-CLL. However, lack of association between tonic BCR features and clinical patterns indicates that tonic BCR signaling may not be of clinical relevance. By contrast, responsiveness to BCR stimulation seems to have clinical significance. Stimulation of BCR was achieved by using anti-IgM antibodies, which mimic in vitro encounters with antigen. In vitro cross-linking of the BCR with anti-IgM in B-CLL cells has been shown to elicit increases in intracellular calcium and global protein tyrosine phosphorylation,[34,35] and augmentation of the phosphorylation levels of signaling proteins downstream of BCR signaling pathways, specifically, SYK, ERK and AKT.[34–37] Signaling events downstream of the BCR are heterogeneous among patients with B-CLL. B-CLL cells with unmutated IGHV genes and poor prognosis display a higher responsiveness to BCR stimulation, while B-CLL cells with mutated IGHV genes and indolent disease show a weaker and less frequent BCR responsiveness. However, B-CLL cells that are responsive to BCR often show a partial responsiveness, with effective activation of only certain signaling pathways. For instance, there is weak activation of p38 and c-JNK whereas the activation of NF-κB is heterogeneous compared with B cells from healthy donors.[31,37] This partial activation of BCR downstream pathways is reminiscent of anergic mouse B-cell features. Interestingly, BCR unresponsiveness in B-CLL is associated with constitutive activation of ERK and NFAT, mirroring again features of anergic transgenic mouse models. These features might be considered a molecular signature of in vivo cellular anergization in patients with chronic lymphocytic leukemia.
Most B-CLL cells express both IgM and IgD molecules at the membrane, and the two isotypes share the same antigen-binding specifities. Whereas responses mediated by IgM stimulation are heterogeneous across patients and appear to be involved in the pathogenesis and progression of B-CLL, the majority of patients with B-CLL respond to IgD stimulation with increases in SYK and ERK phosphorylation, irrespective of prognostic markers and clinical outcome.[8,39] Furthermore, signaling responses to IgM stimulation are prolonged while those mediated by IgD are transient. Differences in the kinetics of signaling responses affect different biological readouts: signaling mediated by IgM induces cell cycle activities (via activation of the ERK/MYC pathway) and support cell survival, while IgD signaling does not.[40,41] Overall, the function of IgD in B-CLL is enigmatic and still to be elucidated.
Expert Rev Hematol. 2012;5(3):341-348. © 2012 Expert Reviews Ltd.