Previously we could validate SYK inhibitor specificity by performing a protein tyrosine kinase activity assay, demonstrating that the SYK inhibitor R406 only decreased the kinase activity of SYK but not of ZAP70.[16] Phosphoinositide 3-kinase (PI3K) is a downstream target in the CD38 pathway and its activity is reflected by the amount of AKT phosphorylation.[15] As expected, AKT phosphorylation was significantly induced upon CD38 stimulation using the agonistic anti-CD38 mAB IB4 in primary CLL cells, however, adding the SYK inhibitor R406 largely abrogated this effect (Fig 2A, n = 8, p<0.05). Here, CD38 is linked to B-cell chronic lymphocytic leukemia.