Schematic of proposed mechanism of action and patient stratification strategy for PIM inhibitors. (A) PIM kinases augment the tyrosine kinase-mediated STAT5 activation and MYC stability to achieve maximal proliferative effect. Abnormally activated upstream tyrosine kinases stimulate STAT5 activity and stabilize MYC protein but require PIM kinases to achieve maximal and sustained activation of these oncoproteins. (B) In the presence of anomalous tyrosine kinase activation, addition of a PIM inhibitor diminishes the activity of STAT5 and shortens the stability of MYC. A specific and potent PIM inhibitor may suppress serine phosphorylation events on STAT5 and MYC to attenuate the tyrosine kinase-mediated activation. (C) Incorporation of CD25 and genetic assessment of tyrosine kinases as patient selection biomarkers in a clinical trial.