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BCR internalization and signaling in CLL
recently proliferated LN emigrants,28 with the CXCR4dimCD5bright subset showed that both the LN and recent emigrants express higher levels of sIgM, however, no consistent difference in BCR internalization efficiency was observed. This was a surprising finding given that BCR activation takes place in the LN and should result in the downregulation of sIgM. Finally, long-term in vivo inhi- bition of BCR signaling using BTKis resulted in an increase in the number of CLL cells exhibiting features of anergy, including a reduction in sIgM expression and signaling competence as well as an increase in the efficiency of BCR internalization.
These results have a number of implications. First, it is
clear that in CLL, BCR internalization is uncoupled from downstream signaling, since anergic CLL B cells internal- ize their BCRs more efficiently than non-anergic cases and normal B cells. These findings are in keeping with previ- ous murine studies which showed that reduced surface BCR expression and uncoupling of signaling in normal anergic B cells is due to rapid internalization and retention in endosomes.30 Since an enhanced accumulation of BCR in endosomes was observed in every patient studied, the present results show that, at least in this respect, all cases of CLL show some features of anergy.
Second, although CD79B is known to associate with sIgM and is essential for the export of IgM to the cell sur-
Figure 4. Proposed mechanism for the dissociation of BCR signaling and internalization in CLL. Two alternative configurations of the BCR are proposed. Type 1 in which CD79B and surface (s)IgM are already closely associated or become associated following ligand binding. This form of the receptor can transduce downstream signals, but is not internalized until the subunits dissociate. Type 2 BCRs do not contain CD79B either before or after ligand binding. These receptors therefore cannot signal but can become internalized. Possible BCR compositions in anergic and non-anergic CLL are illustrated. In anergic CLL, both sIgM and sCD79B levels are low and there is little potential for association between the two either before or after ligand binding. In this scenario, downstream BCR signaling is minimal but internal- ization is efficient. In non-anergic cases of CLL, both sIgM and sCD79B levels are higher and there is a greater likelihood of the two becoming associated. Signaling is thus relatively more efficient but the capacity for internalization is less. CLL: chronic lymphocytic leukemia; BCR: B-cell receptor.
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