Preclinical Study Finds Tumor Suppressor May Actually Fuel Aggressive Acute Myeloid Leukemia
A study published this week in the Journal of Clinical Investigation suggests that blocking the RUNX1 protein normally credited with suppressing leukemia may be a promising therapeutic strategy for acute myeloid leukemia.
Transcription Factor RUNX1
Researchers from Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio, targeted a transcription factor known as RUNX1, which also plays an important role in helping regulate the normal development of blood cells. The researchers were surprised to discover in their laboratory tests that RUNX1 was supporting the growth of acute myeloid leukemia fueled by fusion proteins.
"RUNX1 is generally considered a tumor suppressor in myeloid neoplasms, but our study found that inhibiting its activity rather than enhancing it could be a promising therapeutic strategy for acute myeloid leukemias driven by fusion proteins," said James Mulloy, PhD, a Researcher in the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's and lead investigator.
Acute myeloid leukemia develops and progresses rapidly, requiring prompt treatment with chemotherapy, radiation, or bone marrow transplant. These treatments can be risky or only partially effective depending on the patient as well as the variation and progression of disease. Researchers are searching for improved treatment strategies, including targeted molecular approaches that could potentially be more effective and carry fewer side effects.
The investigators tested their finding in a genetic mouse model of acute myeloid leukemia (developed by Dr. Mulloy's laboratory) that is driven by fusion proteins and a mixed-lineage leukemic gene called MLL-AF9. The researchers genetically inhibited both RUNX1 and an associated protein called core-binding factor subunit beta (Cbfb). By doing so, the researchers were able to stop the development of leukemia cells, demonstrating the potential viability of RUNX1 as a therapeutic target.
Paul Liu, MD, PhD, at the National Cancer Institute also collaborated on the study and developed a small molecule that specifically inhibits RUNX1. Using this inhibitor, the researchers showed that the acute myeloid leukemia cells were more sensitive than normal blood cells, indicating the inhibitor may be useful in the future as a therapy for patients with acute myeloid leukemia.
The research team continues to test inhibition of RUNX1 in acute myeloid leukemias driven by fusion proteins and in other blood disorders involving RUNX1. Their goal is to see how their findings might eventually lead to potential treatment of human disease.
Funding support for the research came, in part, from the National Institutes of Health's National Center for Research Resources (1UL1RR026314-01), a U.S. Public Health Service Translational Trials Development and Support Laboratory award (MO1RR08084), CancerFreeKids Foundation for Cancer Research, the Intramural Research Program of the National Human Genome Research Institute, NIH (HG000030-18), a Cincinnati Children's Clinical and Translational Science Award and the Leukemia and Lymphoma Society.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
