During the past decade, data on the putative
roles of STAT
proteins in mediating gene expression without
tyrosine phosphorylation have been accumulating.
In 2005, the identification
of an activating mutation in JAK2 (the V617F mutation) as a STAT5 - activating and disease - causing genetic alteration in a significant proportion
of patients with myeloproliferative neoplasms (MPNs) has emphasized the oncogenic
role of the JAK
tyrosine kinases in hematologic malignancies.2 — 5 JAK2 is a member
of the Janus
tyrosine kinase family comprising three other mammalian non-receptor
tyrosine kinases (JAK1, JAK3 and TYK2) that associate with cytokine receptors lacking intrinsic kinase activity to mediate cytokine - induced signal transduction and activation
of STAT transcription factors.6 All JAKs share a similar
protein structure and contain a
tyrosine kinase domain at the C - terminus flanked by a catalytically inactive pseudokinase domain with kinase - regulatory activity, by an atypical SH2 domain and by a FERM domain that mediates association to the membrane - proximal region
of the cytokine receptors.7, 8 Soon after the discovery
of JAK2 V617F, we and others described that activating JAK1 mutations are relatively common in adult patients with T - cell acute lymphoblastic leukemia (ALL) and participate in ALL development allowing for constitutive activation
of STAT5.9 — 11 Several STAT5 - activating JAK1 mutations were also reported in AML and breast cancer patients.10
Here, we have shown for the first time that the unphosphorylated STAT2 could play an important
role in RIG - G gene expression by interacting with IRF - 9, further reinforcing the idea that STAT
proteins could function as transcription factors in the absence
of tyrosine phosphorylation.