Targeting the interplay between signaling and transcriptional dysfunction in myeloid leukemias
Oregon Health & Science University
Project Term: July 1, 2022 - June 30, 2027
Our research program is focused on understanding the intersection between signaling and transcriptional dysfunction in myeloid leukemias. We leverage murine models, cell lines and human samples to uncover how biological context shapes the manifestation of oncogenic programs at the molecular level. Our long-term goal is to harness this knowledge to identify multipronged therapeutic strategies that improve outcomes for patients with myeloid malignancies.
The Maxson laboratory is working to understand how mutations in genes turn normal blood cells into blood cancers. A focus of our research program had been on mutations in a gene called CSF3R. Normally, CSF3R is turned on when your body needs more neutrophils—a type of white blood cell. When CSF3R is mutated, it gets stuck “on” all of the time. This causes too many neutrophils to be made, resulting in blood cancer. We previously discovered that 90 percent of patients with a disease called chronic neutrophilic leukemia have mutations in CSF3R. These mutations can also occur in other types of leukemia, such as pediatric acute myeloid leukemia, where they are associated with more aggressive cancer. Although CSF3R mutations are instrumental in causing blood cancer, we know that they do not act alone. Other gene mutations occur along with CSF3R mutations in blood cancer cells. We are investigating how these other mutations work together with CSF3R to cause cancer. We had previously identified a drug that shuts off mutated CSF3R, which was used in clinical trial. Although the results of this trial were promising, this drug does not cure disease in all patients. Patients with more mutations tend to have a worse response to treatment. Therefore, additional drugs will likely need to be used in the majority of patients to stop the cancer from coming back. Our long-term goal is to identify drug combinations that provide long-lasting remissions for patients with leukemias.