Novel Approaches to AML Differentiation Therapy

Background
Children with acute myeloid leukemia (AML) are in desperate need. Survival of ids with AML remains poor because our treatments haven't changed much in 30 years. AML is a disease of DNA – mutations found in leukemia DNA are not seen in normal blood cells. However, we think that the physical structure of DNA itself could also be important in leukemia development. If the DNA in a cell was stretched out, it would be six feet long, yet it has to be tightly packed to fit inside the head of a pin. When we looked at leukemia under the microscope, the DNA was not as tightly wound as it should be. We suspected that AML might result from problems in DNA packing. We found that one protein often increased in AML cells directly loosens DNA winding. This especially occurs in kids with Down syndrome or in situations where leukemias have extra copies of chromosomes. When the DNA is “unpacked,” the cell loses its ability to develop normally, leading to AML.

Project Goal
In this project, we propose a new idea in leukemia research: AML may result from unwinding of tightly packed DNA. Drugs that reverse this process could offer new treatments. We will use cutting-edge techniques to understand how DNA unpacking promotes leukemia and test if drugs that target DNA packing kill leukemia cells. We hope our work will lead to new clinical trials for children with leukemia, using drugs that are more effective and less toxic than our current therapies.