In this work we present evidence that MPN cells exposed to ruxolitinib, that effectively reduced phosphorylation of the key Y694 tyrosine residue of STAT5a, demonstrated persistence of phosphorylation at the serine residues of STAT5b; we also show that these residues are under the control of the PI3K/mTOR signaling and resulted specifically targeted by inhibitors acting at different levels of the pathway. Here, STAT5B is linked to myeloproliferative neoplasm.