Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth

Protein tyrosine kinases play a major role in promoting cell growth, and th eir activity in solid tumors is well established. Inhibitors of protein tyr osine kinases are now in advanced clinical trials for the treatment of brea st and brain cancers. Because Src-related PTK have been shown to be activat ed in leukemic cell lines, we studied their activation in human myeloid leu kemia. Blasts from the majority of patients with acute leukemia showed cons titutive activity of the Src kinase Lyn. In contrast, no patient samples sh owed constitutive activation of Jak2. Genetic and pharmacologic targeting o f Lyn was used to determine its contribution to leukemic cell growth. Antis ense Lyn oligonucleotide treatment resulted in the inhibition of tritiated thymidine incorporation following GM-CSF stimulation of the factor-dependen t line MO7e. The Src kinase inhibitor PD166285 inhibited the growth of huma n leukemic cell lines and leukemic blasts. When combined with doxorubicin, an additive effect on the inhibition of leukemic cell growth occurred. Thes e studies demonstrate the importance of Src kinases in promoting leukemic c ell growth and suggests that further development of agents which target Src kinases and their inclusion in multidrug regimens are warranted for novel therapies of myeloid leukemia.