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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2440-2448
NEOPLASIA
ARG tyrosine kinase activity is inhibited by STI571
Keiko Okuda,
Ellen Weisberg,
D. Gary Gilliland, and
James D. Griffin
From the Department of Adult Oncology, Dana Farber
Cancer Institute; the Department of Medicine/Division of Hematology,
Brigham and Women's Hospital; and the Department of Medicine, Harvard
Medical School, Boston, MA.
The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces
hematologic remission in most patients with chronic myeloid leukemia.
In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF) receptor, and c-KIT, but it does not inhibit SRC family kinases,
c-FMS, FLT3, the epidermal growth factor receptor, or
multiple other tyrosine kinases. ARG is a widely expressed tyrosine
kinase that shares substantial sequence identity with c-ABL in the
kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL.
A TEL/ARG fusion was constructed to determine whether ARG can be
inhibited by STI571. When expressed in the factor-dependent murine
hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily
phosphorylated on tyrosine, increased tyrosine phosphorylation of
multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with
BCR/ABL, TEL/ABL, TEL/PDGFR, or TEL/ARG were then compared. STI571
inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells
expressing BCR/ABL, TEL/ABL, TEL/PDGFR, and TEL/ARG with an
IC50 of approximately 0.5 µM in each case, but it had no
effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells
with IL-3 completely prevented STI571-induced apoptosis in these cells,
similar to what has been observed with BCR/ABL- or TEL/ABL-transformed
cells. These results indicate that ARG is a target of the small
molecule, tyrosine kinase inhibitor STI571.
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