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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4354-4364
Fusion of the ets Transcription Factor TEL to Jak2 Results in
Constitutive Jak-Stat Signaling
Jen M.-Y. Ho,
Bryan K. Beattie,
Jeremy A. Squire,
David A. Frank, and
Dwayne L. Barber
From the Division of Cellular and Molecular Biology, Ontario Cancer
Institute, Toronto, Ontario, Canada; the Department of Laboratory
Medicine and Pathobiology, Toronto Hospital, Toronto, Ontario, Canada;
the Departments of Medical Biophysics and Laboratory Medicine and
Pathobiology, University of Toronto, Toronto, Ontario, Canada; and the
Dana-Farber Cancer Institute, Boston, MA.
To study constitutive Janus kinase signaling, chimeric
proteins were generated between the pointed domain of the ets
transcription factor TEL and the cytosolic tyrosine kinase Jak2. The
effects of these proteins on interleukin-3 (IL-3)-dependent
proliferation of the hematopoietic cell line, Ba/F3, were studied.
Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion
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. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or
Jak2 JH2+JH1 domain fusions) were constitutively
tyrosine-phosphorylated but did not affect phosphorylation of
endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the
constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as
determined by detection of phosphorylation using activation-specific
antibodies and by binding of each protein to a preferential GAS
sequence in electrophoretic mobility shift assays. Elucidation of
signaling events downstream of TEL-Jak2 activation may provide insight
into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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