The NRAS palmitoylation cycle as a therapeutic target in pediatric leukemia
Acute myeloid leukemia (AML) is harder to cure than acute lymphoblastic leukemia (ALL) and most other types of childhood leukemia and lymphoma. AML treatments are toxic and requires patients and their families to spend up to a year in the hospital to minimize risks of infection and bleeding. Many children with AML need bone marrow transplantation as part of their initial treatment, and nearly every AML patient will undergo a transplant if their leukemia relapses. Childhood AML survivors often have side effects later in life from their treatment, including heart disease, infertility, and additional cancers. We need new treatments for AML that are less toxic and more effective. Mutations in a gene called NRAS are very common in pediatric AML. These altered genes encode mutant N-Ras proteins that tell the leukemia cell to grow and divide much more quickly than healthy cells. If we could shut down this abnormal N-Ras signaling, it would stop the leukemia from growing but would leave healthy cells relatively unaffected. Unfortunately, no approved drugs exist that target the mutant N-Ras proteins found in AML and other pediatric cancers.
Project Goals
N-Ras is made inside the cell and then shipped to the cell surface, where it anchors to the cell membrane thanks to a protein modification called palmitoylation. We know that if you block palmitoylation by introducing a single mutation to the NRAS gene, you prevent N-Ras anchoring, disrupt signaling, and stop the growth of leukemia. This means proteins that palmitoylate N-Ras (called palmitoyltransferases) should be excellent targets for drug development. However, we still don't know the full family of N-Ras palmitoyltransferases. Our project addresses this critical research gap through two sets of experiments: (1) we overexpress a set of candidate palmitoyltransferases in leukemia cells and measure N-Ras palmitoylation levels; (2) we block expression of candidate palmitoyltransferases in leukemia cells and see if they stop growing. The results of these experiments will identify the complete set of targetable N-Ras palmitoyltransferases, and therefore allow us to screen and develop new drugs for children with AML.
