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

Maria Teresa Scupoli; Giovanni Pizzolo

Disclosures

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

In This Article

Cell Survival & Apoptosis

According to the proposed model, BCR signaling would suppress apoptosis in vivo, thereby contributing to accumulation of leukemic cells and favoring secondary genetic alterations. Indeed, several experiments in vitro have shown that BCR stimulation with anti-IgM is able to transmit survival signals into B-CLL cells that are associated with enhanced activation of the NF-κB, ERK and AKT pathways.[37,45,46]

The NF-κB pathway plays a crucial role in the pathogenesis of many cancers owing to its ability to modulate cell survival.[33] The NF-κB transcription factors regulate the expression of several anti-apoptotic genes including BCL2 and BCLXL, both of which have been involved in the inhibition of apoptosis in B-CLL.[47] NF-κB proteins are constitutively expressed in cells of patients with B-CLL,[48,49] and the NF-κB protein RELA has been proposed to be an independent prognostic marker of survival in B-CLL.[50] Stimulation of BCR with anti-IgM induces a subtle increase in NF-κB binding activity in B-CLL cells, which is associated with augmented transcription of the NF-κB target anti-apoptotic gene BCL2.[46] The effects of BCR stimulation on NF-κB activity in B-CLL are significantly enhanced when anti-IgM antibodies are combined with anti-CD40 antibodies.[46] Moreover, lymph node (LN)-resident B-CLL cells exhibit gene-profiling motifs consistent with enhanced activation of BCR and NF-κB, if compared with peripheral blood-derived B-CLL.[30] Therefore, although in vitro BCR stimulation with anti-IgM induces a slight activation of NF-κB in a small fraction of patients with B-CLL,[37] these data suggest that the BCR-induced NF-κB activation in the LN microenvironment may have a relevant pathophysiological and clinical significance in vivo.

The RAF/MEK/ERK pathway regulates the expression and function of several proteins that promote cell survival. Examples include the proapoptotic BCL-2 family BH3-only proteins BAD and BIM, which are inhibited by the ERK pathway.[51] Constitutive phosphorylation of ERK is present in almost half of the cases of chronic lymphocytic leukemia and has been associated with BCR unresponsiveness.[32] Interestingly, it has been described that increased ERK phosphorylation in response to anti-IgM stimulation is a feature of B-CLL with poor prognostic markers, and it is associated with a shorter clinical progression,[35,52,53] thus suggesting that this signaling node plays a key role in B-CLL progression. Indeed, although the involvement of ERK in B-CLL proliferation mechanisms has been recently suggested,[40] the role of ERK in CLL survival has not yet been fully clarified.

The PI3K/AKT pathway represents a key mechanism controlling cell survival in many cell types, including B-CLL.[45,51] Activated AKT inhibits the proapoptotic protein BAD while activating the BCL-2-related protein myeloid cell leukemia-1 (MCL-1).[54,55] In addition, AKT induces the expression of prosurvival genes, such as BCLXL, apparently by a crosstalk between AKT and NF-κB pathways.[21–23] Originally modeled as linear, independent routes, these signaling pathways are now considered to intersect at different levels to regulate each other and converge to downstream functions.[21,22,45,51] In B-CLL, MCL-1 is associated with chemoresistance and the presence of poor prognostic markers.[37,46,50,56] In addition, it appears to be a major component of the survival pathway activated in B-CLL cells by the PI3K/AKT pathway.[45,57] Moreover, pharmacological inhibition of PI3K completely abrogates MCL-1 induction and impairs survival in BCR-stimulated cells.[46]

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