Signaling Pathways Activated by B-Cell Receptor in CLL

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.^[32] It is known that tonic signaling of BCR is required by normal B cells to properly develop, be maintained and survive.^[33] 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^[31] 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.^[8] 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.^[38] Interestingly, BCR unresponsiveness in B-CLL is associated with constitutive activation of ERK and NFAT, mirroring again features of anergic transgenic mouse models.^[38] 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.^[39] 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.

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