BCR/ABL inhibition by an escort/phosphatase fusion protein

Cellular transformation by the BCR/ABL oncogene depends on the ABL-encoded tyrosine kinase activity. To block BCR/ABL function, we created a unique ty rosine phosphatase by fusing the catalytic domain of SHP1 (SHP1c) to the AB L binding domain (ABD) of RIN1, an established binding partner and substrat e for c-ABL and BCR/ABL. This fusion construct (ABD/SHP1c) hinds to BCR/ABL in cells and functions as an active phosphatase. ABD/SHP1c effectively sup pressed BCR/ABL function as judged by reductions in transformation of fibro blast cells, growth factor independence of hematopoietic cell lines, and pr oliferation of primary bone marrow cells. In addition, the leukemogenic pro perties of BCR/ABL in a murine model system were blocked by coexpression of ABD/SHP1c, Both the "escort" function provided by ABD and the inhibitor fu nction provided by the phosphatase of SHP1 c were necessary for effective B CR/ABL interference, Expression of ABD/SHP1c also reversed the transformed phenotype of K562, a human leukemia-derived cell line. These results have d irect implications for leukemia therapeutics and suggest an approach to blo ck aberrant signal transduction in other pathologies through the use of app ropriately designed escort/inhibitors.