how to better define and identify certain genetic mutation and their relationship to cancer development

Dr. Spencer proposes to model the effects that specific cancer mutations have on epigenetic gene regulation using induced pluripotent stem cells derived from AML patients that harbor mutations in genes known as IDH1 and IDH2. These mutations occur in ~20% of AML patients, and are known to alter gene expression, such as DNA methylation, an important contributor to gene regulation. However, the specific gene ‘targets’ that are affected by these mutations in AML cells are unknown. In addition, it is currently unclear how the DNA methylation changes contribute to the development of AML.

The objectives of this project are to identify the direct effects of these mutations on DNA methylation and gene expression in human cells, and then to determine whether there are specific target genes in blood cells. The induced pluripotent stem system is ideal for addressing these questions, because the cells can be grown and manipulated in the laboratory, like cancer cell lines, but they have the ability to differentiate into a variety of normal cell types, including blood cells. Therefore Dr. Spencer’s lab has an opportunity to define the initial IDH-associated changes in DNA methylation, and gene expression, in human blood cells, before fully developed AML occurs.

The results from this study will shed light on the events that lead to AML with IDH mutations, and inform future studies of specific genes that are involved in AML initiation. Because this novel model system uses human cells, the findings can be directly correlated, and confirmed, using data from primary AML samples.

The fact that IDH mutations are now the targets of FDA-approved drugs for AML patients is also highly significant for this research, since results from these experiments may yield additional genes and/or pathways that can be targeted therapeutically. The experimental systems developed in this project, and the findings they generate, will also establish a solid foundation upon which future research projects can be built.