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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1758-1765
NEOPLASIA
TEL/platelet-derived growth factor receptor  activates
phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate
the cell cycle
Jamil Dierov,
Qing Xu,
Raia Dierova, and
Martin Carroll
From the Division of Hematology and Oncology,
University of Pennsylvania, Philadelphia, PA.
TEL/platelet-derived growth factor receptor  (PDGFR) is the
protein product of the t(5;12) translocation in chronic myelomonocytic leukemia. TEL/PDGFR transforms interleukin-3 (IL-3)-dependent Ba/F3
and 32D cells to IL-3 independence and induces a murine myeloproliferative disease in a bone marrow transplantation
model of leukemogenesis. The fusion protein encodes a constitutively activated, cytoplasmic tyrosine kinase that activates multiple signal
transduction pathways. To identify the signaling pathways that are
necessary for transformation by TEL/PDGFR, transformed Ba/F3 and 32D
cells were studied. TEL/PDGFR activates the kinase activity of
phosphatidylinositol-3 (PI3) kinase and stimulates phosphorylation of
its downstream substrates, including Akt and p70S6 kinase. Activation
of this pathway requires the kinase activity of TEL/PDGFR and is
inhibited by the PDGFR inhibitor, STI571. Furthermore, inhibition of
PI3 kinase with the pharmacologic inhibitor, LY294002, inhibits growth
of the transformed cells. Treated cells arrest in the G1 phase of the
cell cycle within 16 hours but do not undergo apoptosis. To study the
mechanism of cell cycle arrest by LY294002, the activity of the cdk4
complex, which regulates the transit of cells from the G1 to S phase in
hematopoietic cells, was examined. Both STI571 and LY294002 lead to a
decrease in the activity of cdk4 kinase activity and a decrease in
expression of both Cyclin D2 and Cyclin E within several hours. These
studies demonstrate the presence of a signaling pathway from
TEL/PDGFR to PI3 kinase and subsequently to regulation of the
cdk4 kinase complex. Activation of this pathway is necessary for
transformation by TEL/PDGFR.
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