Beckman Research Institute of the City of Hope
Project Term: July 1, 2017 - June 30, 2022
Acute myeloid leukemia (AML) is a type of very fatal disease (>70% of patients cannot survive 5 years with current therapies) and improved therapies are urgently needed. Here we will conduct a series of studies to define the role of TET1, a DNA demethylase (“eraser”), in the pathogenesis of AML, and to reveal the underlying molecular mechanisms. The success of our study will not only provide novel insight into AML pathogenesis, but may also lead to the development of improved novel therapies.
Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematopoietic malignancies. Thus, it is urgent to better understand the mechanisms underlying the pathogenesis of AML, and on the basis of such understanding, to develop novel therapies with higher efficacy and minimal side effects to treat AML. The properties of cancer are often determined by the proteins that are expressed from information provided by the genes in the cell. Expression of information from genes is regulated in part by chemical modifications of the DNA in the gene, in a process called “epigenetic regulation.” One such modification is called methylation. A family of proteins involved in epigenetic regulation are the 3 TET proteins, which ultimately affect the methylation status of critical genes. TET proteins are traditionally thought to be negative regulators of tumor growth. However, in contrast to this tumor suppressive role, we recently reported that TET1 is highly expressed in certain subtypes of AML, suggesting an opposite role for TET1, the promotion of tumor growth. We are currently studying the mechanisms by which TET1 promotes tumorigenesis and how we might use this information to develop a novel approach to treat AML. Some central questions are to understand how tumors develop, how they are maintained after they develop, and how the leukemia stem cells provide a reservoir for continued tumor development in a patient. Therefore, we seek to understand the role of TET1 in both the development and maintenance of the AML types that overexpress TET1, and the role of TET1 in the leukemic stem cells. In addition, we are studying the critical target genes that are affected by TET1, which will provide further insight into the role of TET1 in AML. Lastly, we are examining ways to therapeutically target TET1 using mouse models of AML. The success of our studies will provide novel insights into our understanding of the critical role of TET1 in AML and may also lead to the development of novel and more effective therapeutic approaches to treat the AML.