Routes to persistent activation of Stats in cancer cells. Stat proteins, in particular Stat3,are persistently activated in a wide variety of different cancers. Explanations for Stat activation are potentially quite varied and include over-expression or dysregulation of kinases or inhibition of the negative regulators. Some examples are listed in red. Jak kinases are indicated as blue ovals. The TEL-JAK fusion protein is constitutively active as a kinase and leads to AML through its effects on STATs 1, 3, or 5. The oncogenic G-protein subunit G_αo, associates with Jak proteins, leading to Stat3 hyperactivation and the transformation of NIH3T3. Overexpression and dysregulation of the EGFR and its ligand TGF-α stimulates the receptor’s intrinsic tyrosine kinase activity and those of the associate Jak and Src protein kinases, thereby inducing persistent Stat3 activity in squamous cell carcinomas. Overexpression and dysregulation of the IL-6 receptor and production of its ligand IL-6 stimulates Stat 3 activity in multiple myeloma. Abnormal regulation of the oncogenic proteins Src and Abl likewise causes excess. Stat3 phosphorylation in sarcomas and chronic myelogenous leukemia, among other malignancies. SOCS1 gene methylation and silencing constitutively activates JAKs1 and 2 and leads to persistent STAT3 phosphorylation in hepatocellular carcinomas. Loss of PIAS3 expression allows for unregulated STAT3 activity in anaplastic large cell lymphoma.