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Decipher and Target AML Cell Dependency on Epigenetic Mutations

G. Greg Wang

G. Greg Wang


The University of North Carolina at Chapel Hill

Project Term: July 1, 2018 - June 30, 2023

The goal of our program aims to understanding the general roles of DNA methylation machineries in epigenetic regulation and cancerous transformation seen in hematological cancers. Routinely, we take a set of integrated biochemical, genomics, oncology, and medicinal chemistry approaches to tackle the broad and critical questions in this field. Our findings shall not only promote current understanding of how hematological malignancies occur but also help develop novel therapeutic approaches.

Lay Abstract

Acute myeloid leukemia (AML) is a common type of blood cancer and exhibits poor prognosis in the clinic,¬¬ demanding new treatment strategies. In a recent advancement, direct sequencing of cancer samples has unveiled the mutational landscape of human AML genomes. The most frequently mutated genes include those encoding a set of cellular enzymes that cause chemical modification of DNA or DNA-associated proteins, including the DNMT3A gene. The modifications these enzymes cause provide instructive information for cells to interpret the genetic information. Cancer cells ‘hijack’ and ‘manipulate’ this system to gain growth advantages, becoming increasingly malignant over years of evolution in the human body. This complex picture of how genes are affected by DNMT3A mutations as well as how the effects leads to AML is far from complete. My research lab seeks to understand the mechanisms and pathways by which mutation of the DNMT3A gene mediates initiation and progression of AML. Towards this goal, we have established several cell- and animal-based models in which DNMT3A mutation is crucial for developing AML, either alone or in addition to another gene mutation associated with AML. We will be using cutting-edge gene-editing (CRISPR/cas9) and genomic profiling approaches to delineate how mutant DNMT3A causes aberrant changes in either chemical modification of DNA or subsequent gene-expression programs. We will further study which effected genes or pathways are crucial for mediating formation of aberrant blood cells that ultimately lead to leukemia development. Lastly, we are carrying out discovery-based small-molecule screening to identify drug-like compounds that are effective in killing AML cells carrying mutant DNMT3A. We are excited about this research project, and the likelihood of success is strong due to our previously published data and preliminary studies. Additionally, we are collaborating with a set of outstanding collaborators across the country who are experts in enzymatic studies, drug development, and AML treatment. The successful completion my research project should promote a greater understanding of how human AML develops, as well as yield innovative therapeutics for a better AML treatment.

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