Mechanistic Insights into TET-Mediated Demethylation in Leukemia

University Of Chicago, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): Recently, mutations in the TET family of oxygenases have been described in a subset of acute myeloid leukemias (AML). TET enzymes catalyze the addition of a hydroxyl group to methylated cytosine (5mC) within DNA to generate 5-hydroxymethylcytosine (5hmC). Additionally, these enzymes can further oxidize 5hmC to produce 5-formylcytosine (5fc) and 5-carboxylcytosine (5caC), which are the key intermediates in a newly defined active demethylation pathway in mammals. We hypothesize that the disruption of demethylation is a key contributor to the leukemic phenotype in TET-mutant hematopoiesis. To test our hypothesis, we plan to use novel techniques to identify the locations of 5hmC and 5fC on a genome-wide scale. Additionally, we will identify genome-wide occupancy maps for TET1 and TET2, as well as thymine DNA glycosylase, the enzyme responsible for removing 5fC and 5caC from DNA to allow for replacement with an unmethylated cytosine. Along with global gene expression analysis, in the presence and absence of TET1/2, these datasets will point us to the genes that are most significantly and directly affected by loss of specific TET enzymes in hematopoiesis. Finally, we will test the role of these identified genes in hematopoietic cells and validate our findings in primary human AML samples.