CLL cells have an aberrant phenotype that includes IgM downregulation, reduced responsiveness to BCR ligands, reduced expression levels of CD21, above-baseline intracellular Ca2+, and activation of BCR pathway kinases, as well as negative feedback regulation, including SHP-1 activation similar to the phenotype of anergic autoreactive B-cells (169, 170). Here, BCR is linked to B-cell chronic lymphocytic leukemia.