The major cause of fatalities in acute myeloid leukemia (AML) is disease relapse, resulting in no more than 50% five-year survival even when the most intensive chemotherapy is used. These relapses reflect de novo or developed chemoresistance of the cancer cells. Acute myeloid leukemia (AML) cells elicit perturbations in signaling networks that mediate chemoresistance, exemplified by receptor tyrosine kinase Flt3 mutations in more than 30% of AML cases. This project aims to characterize intracellular signa ling systems in normal and chemoresistant leukemic stem cells in vivo to reveal cancer-specific signaling aberrations. We will utilize proteomic approaches to map intracellular signaling networks in search for improved or novel therapy development. Our i n vivo imaging techniques will facilitate the subsequent validation of these signaling mechanisms in intact animals.
We will prepare a collaboration with M.D. Ph.D. Tore Eid at Yale University on neurotoxic effect of high dose cytarabin therapy (see encl osed letter of intent). The working hypothesis is that erythropietin may protect against the detrimental effectof cytarabin on the central nervous system, and that erythropoietin will allow the use of high dose cytarabin in the patient age groups above 60 years.