Gene alterations affecting elements of PI3K signaling pathway do not appear to be sufficient to explain the extremely high frequency of PI3K signaling hyperactivation in leukemia. It has been known for long that PTEN phosphorylation at the C-terminal tail, in particular by CK2, contributes to the stabilization and simultaneous inhibition of this critical tumor suppressor. However, direct evidence of the involvement of this mechanism in cancer has been gathered only recently. It is now known that CK2-mediated posttranslational, non-deleting, inactivation of PTEN occurs in T-ALL, CLL and probably other leukemias and solid tumors. To explore this knowledge for therapeutic purposes remains one of the challenges ahead.