Role of ZAP70 in promoting increased malignant cell fitness in chronic lymphocytic leukemia. Weak tonic signals from the B-cell receptor (BCR), generated by an unclear mechanism, influence ZAP70 to stimulate constitutive activation of AKT, some protein translation, and enhanced transcription of the genes coding for CCL3, CCL4, IL4I1, and MYC. Released CCL3 and CCL4 can stimulate migration of monocytes and T cells into proliferation centers (the former becoming macrophages that serve as nurse-like cells), and these cells provide a supportive microenvironment. In this context, ZAP70 serves to enhance malignant cell survival in CLL. If BCR comes into contact with antigen, strong signals ensue that stimulate association of ZAP70 with ribosomal proteins (such as RPS-17), where the kinase function of ZAP70 may play a role and enhance protein translation. At the same time, the BCR signaling pathway is activated where AKT shows strong activation, leading to increased expression of MYC, but this response is independent of ZAP70. Nevertheless, the outcome of such strong signaling from the BCR is enhanced cellular proliferation. Increased fitness of CLL cells expressing ZAP70 in terms of survival and proliferation are therefore likely to contribute to progressive disease, explaining why expression of this tyrosine kinase is linked with poor prognosis. mTOR, mammalian target of rapamycin; P, phosphate. Professional illustration by Somersault18:24.