Fusion of the ets transcription factor TEL to Jak2 results in constitutiveJak-Stat signaling

To study constitutive Janus kinase signaling, chimeric proteins were genera ted between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleuki n-3 (IL-3)-dependent proliferation of the hematopoietic cell line, Ba/F3, w ere studied, Fusion of TEL to the functional kinase (JH1) domain of Jak2 re sulted in conversion of Ba/F3 cells to factor-independence. Importantly, fu sion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3-dependent proliferation of Ba/F3 cells. A ctive TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 do main fusions) were constitutively tyrosine-phosphorylated but did not affec t phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation r esulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and S tat5 as determined by detection of phosphorylation using activation-specifi c antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events d ownstream of TEL Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein. (C) 1999 by The A merican Society of Hematology.