are changes in the chromatin supporting dna critical to the development of some acute myeloid leukemias?

Dr. Meers is interested in how “epigenetic” processes, which modify the way DNA is used without changing its underlying sequence, affect the development of cancer. More specifically, his expertise is in chromatin, a suite of proteins that act as molecular beads structuring the way DNA is wrapped or bundled within a cell, granting or restricting access to certain parts of the DNA and the proteins that section encodes and therefore creating epigenetic controls. Increasingly, the dysregulation of chromatin has been identified as a key molecular hallmark of cancer, so measuring changes in chromatin that accompany tumorigenesis is of utmost importance. This is especially the case for cancers such as Acute Myeloid Leukemia (AML,) in which proteins that regulate chromatin are perturbed by “driver” mutations early in the life of the cancer, suggesting their importance in cancer onset. With that in mind, the goal of this proposal is to directly measure thousands of chromatin changes in patient AMLs and models thereof to learn how chromatin contributes to the development of their cancers.

Dr. Meers plans to focus on the chromatin modifications caused by a protein called Isocitrate Dehydrogenase (IDH); a substantial number of AMLs show early mutations in a gene that encodes for IDH and with these mutations IDH inhibits enzymes that modify chromatin proteins. He is particularly interested because these enzymes respond by increasing their abundance in AML, which suggests that maintaining the chromatin-modifying function of these enzymes is important for AML to continue and grow. Dr. Meers will use CUT&RUN and CUT&TAG, two epigenetic profiling tools he helped pioneer, to document and cross-reference thousands of chromatin changes across several AML patient samples at once to pinpoint the epigenetic abnormalities that are important for cancer growth. This project will produce comparative and functional maps of changing chromatin in IDH mutant AML; because IDH has unique chromatin enzyme-inhibitory characteristics, the results are likely to significantly increase our understanding of how AML arises in the first place. Additionally, this project will help establish the routine usage of powerful new epigenome profiling tools that can be applied to chromatin and other epigenetic changes across a range of other cancers, allowing scientists to investigate cancer epigenetics as fully as they have cancer genetics.