Less than 50 percent of children with acute myeloid leukemia (AMI) survive despite intensive chemotherapy and marrow transplantation. We have found that a protein known as CREB is overproduced in leukemia stem cells compared to normal stem cells. Our laboratory has demonstrated that CREB increases the growth and survival of myeloid cells. We propose to use a technology, known as RNA interference (RNAi), to "knockdown" CREB in hopes of stopping the growth of leukemia cells. Preliminary studies from our laboratory showed that knocking down CREB levels had a dramatic effect on the growth of myeloid leukemia cell lines. In this proposal, we will use RNAi technology to block CREB's effects on leukemia cells. In Aim 1, we will test the effects of inhibiting CREB on normal bone marrow stem cells to study the role of CREB during hematopoiesis. In Aim 2, we will characterize the effects of RNAi on molecules that activate CREB and promote growth or survival of leukemia cells. In Aim 3, we will test whether RNAi will slow the progression of leukemia in mice. These studies will provide new ways of treating AMI in hopes of improving the survival of children afflicted with this disease. [unreadable] [unreadable] [unreadable] [unreadable]