Testing Small Molecules that Target a Pediatric Leukemia-Associated Oncogene for Chromatin-Modifying Activity
Background
Acute myeloid leukemia (AML) is a cancer of cells that cannot develop into our normal blood cells. AML cells are 'stuck' in the progress of maturing, so they divide in excess. Children with AML have limited treatment options. Current therapies are over 30 years old and are not appropriate for certain subtypes of AML. There is a definite need for newer and better AML treatments. To that end, a new idea from the Lane Lab is that abnormal DNA structure may contribute to AML by blocking cells from maturing. Normally, DNA is packed tightly in the nucleus. This tight packing shields genes from being read when they should not be. In AML cells, DNA is not as tightly wound as other normal immature blood cells. The structure of DNA wound around a protein, like a string around a spool, is called a nucleosome. AML cells have excess of a particular protein called HMGN1, which binds to the nucleosome. The Lane Lab found that when HMGN1 binds to the nucleosome, it stops DNA from being tightly packed and prevents the cell from differentiating. Thus, a logical goal is to find drugs that may stop HMGN1 from binding to the nucleosome. The lab has already found several compounds that bind HMGN1. However, not all these compounds that bind to HMGN1 necessarily stop the protein from binding to the nucleosome.
Project Goal
My role this summer is to test which of the compounds that bind HMGN1, actually stop it from binding the nucleosome. Ultimately a goal of this work is to find new drugs that are more specific and more effective than current AML drugs.
Mentored by Dr. Andrew Lane
Dana-Farber Cancer Institute, Boston, MA
