Zap70 Integrates Bcr-Signaling Into Innate Signaling Pathways In Cll

The recent clinical success with small molecule inhibitors targeting the B cell receptor (BCR) pathway provides unambiguous evidence that signals engaging the BCR play a key role in the pathogenesis of CLL. The binding of CLL cells to a proposed auto-antigen has encouraged many researchers to identify these antigens. This has more recently been challenged by the identification of an internal epitope within the BCR leading to a cell autonomous, antigen-independent activation of the BCR. Overall, the response of CLL cells to a continuous activation of the BCR is anergy. Notably, with respect to different subgroup of patients, M-CLL/ZAP70 negative cases appear to be more “locked” in an anergic state than UM/ZAP70 positive cases. Since investigations in non-malignant B cells suggest that innate signaling-pathways integrate into the BCR-signaling cascade to overcome anergy, we investigated the responses to TLR9 ligation in 57 purified CLL patient samples with regard to the expression of ZAP70, which is considered to amplify signals funneled through the BCR: