ARG tyrosine kinase activity is inhibited by ST1571

The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematolog ic 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)beta receptor, and c-KIT, but it does not inhibit SRC f amily kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multip le other tyrosine kinases. ARG is a widely expressed tyrosine kinase that s hares substantial sequence identity with c-ABL in the kinase domain and coo perates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of le ukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to dete rmine whether ARG can be inhibited by STI571. When expressed in the factor- dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was hea vily phosphorylated on tyrosine, increased tyrosine phosphorylation of mult iple cellular proteins, end induced factor-independent proliferation. The e ffects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGF betaR, or TEL/ARG were then compared, STI571 inhibited tyrosine phosphoryl ation end cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGF betaR, and TEL/ARG with an IC50 of approximately 0.5 muM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 c ells transformed by TEL/ JAK2. Culture of TEL/ARG-transfected Ba/F3 cells w ith IL-3 completely prevented STI571-induced apoptosis in these cells, simi lar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. T hese results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571. (Blood. 2001;97: 2440-2448) (C) 2001 by The Americ an Society of Hematology.