Lay Abstract: Cancers that arise from blood cells, like all cancers, are caused by the accumulation of mistakes in DNA, the blueprints of every cell. These mistakes, or mutations, cause the cell to grow abnormally and eventually become cancer. The cause of DNA mutations is critical to understanding both how cancer develops, and how cancer can be treated. Patterns of DNA mutations in cancers can help identify the causes of mutations. For example, DNA mutations caused by exposure to sunlight result in a specific pattern that can be identified throughout the DNA of skin cancer cells. While sunlight is known to be a DNA mutator that can contribute to cancer development, other causes of DNA mutation patterns are not clearly associated with cancer. A prevalent mutation pattern that is found in human cancer, and specifically blood cancers, appears to be caused by members of the APOBEC3 protein family, which are part of the innate immune system.

The APOBEC3 proteins are normally found in healthy blood cells and are responsible for limiting virus infection by causing mutations in viral DNA. Our prior research determined that when APOBEC3 proteins behave abnormally, they are also capable of mutating DNA in human cells. The goals of our proposal are to determine how other proteins in a cell enable the abnormal activity of APOBEC3 that results in DNA mutations, and whether the mutations caused by APOBEC3 enzymes promote the development of blood cancers such as leukemia and lymphoma.

I am a pediatric oncologist and infectious diseases specialist. I care for children with cancer and infectious complications of cancer therapy. My research goals are designed around the objective of improving care for my patients. My long-term goal is to develop a robust research program focused on determining the causes of DNA mutations that lead to blood cancers. DNA mutations can be inherited at birth or acquired later in life, and my objective is to better understand both types of mutations. Ultimately, we will use that knowledge to ascertain risk factors for the development of blood cancer, and to establish the best treatment options for blood cancers in children and adults.

This Career Development Award from the PRCRP will provide me with crucial resources and mentorship so that I can execute the proposed experiments and advance my career as an independent cancer researcher. I will benefit from the mentorship of Dr. Daniel Link, an internationally known expert on DNA mutations in blood cells. During the funding period, I will improve my skills in important cancer research techniques, including computational DNA mutation analysis and mouse models of blood cancer. I will present and publish my work and will develop collaborations with other investigators, including members of the Virtual Cancer Center (VCC). Through support from the VCC, I will provide mentorship to trainees in my lab at the undergraduate, graduate, and postdoctoral levels, and will encourage trainees to explore careers in cancer research. At the culmination of the award period, our lab will be well-poised to become a leader in the field of blood cancer research.

This award will support the generation of new research tools to study the cause of DNA mutations in blood cancer. The proposed research will benefit patients with blood cancers by identifying how APOBEC3 enzymes cause mutations in DNA, and how those DNA mutations influence the development of blood cancers. Thus, our research will improve understanding of potential risk factors for the initiation and progression of blood cancer. Our initial data suggest that APOBEC3 proteins are a cause of DNA mutations in both childhood and adult blood cancers, thus providing far-reaching applications of our research.

Additionally, this research will investigate methods to exploit the mutations caused by APOBEC3 proteins to promote cancer cell death, thus creating the opportunity to develop new therapies for blood cancer. Studies aimed at how other cellular proteins influence APOBEC3 mutations will lead to identification of treatment strategies that are specific for blood cancers with high APOBEC3 activity. We envision that in the next phase of research these treatment options will be evaluated in animal models, which will form the foundation for clinical trials in human patients. At the Washington University School of Medicine, where our research is performed, there is a fluid interaction between clinical oncologists and cancer researchers which will facilitate the development of our scientific findings into clinical applications for patients.

By studying the effects of APOBEC3 enzymes in cancer, our efforts will directly benefit military families who are affected by blood cancer, including children and adults. The normal function of APOBEC3 enzymes in human cells is to protect against virus infections. By learning more about these enzymes, we will also gain insight into their function as anti-viral agents, which will benefit active duty Service members and their families who have unique risks for infectious disease.