CBF Dysregulation in AML

Dr. Day is a clinician/researcher who focuses on hematologic malignancies; his work in the lab particularly deals with acute myeloid leukemia, an aggressive blood cancer with an overall five-year survival of 30 to 40% in adults. He is particularly interested in how the dysregulation of the core binding factor (CBF) pathway in blood cells promotes AML development and maintenance. CBF is a transcription factor that consists of two proteins: (most often) RUX1 and the CBFB beta subunit. While mutations in CBFB or RUX1 are found in roughly 30% of adult AML patients, Dr. Day’s lab recently found that transcriptional deregulation of RUX1 and CBFB is universal in AML, regardless of mutations, leading to roughly a 50% reduction in CBFB mRNA relative to healthy hematopoietic stem and progenitor cells. Therefore, Dr. Day proposes to understand how reduced CBFB activity promotes AML, and whether it might provide a therapeutic target.

Dr. Day has developed a mouse model with reduced CBFB and has already shown that bone marrow cells with reduced CBFB show a competitive advantage over normal cells, suggesting that leukemic cells with reduced CBFB might have a growth and survival advantage over non-cancerous cells in the bone marrow. With his CRF Young Investigator Award, he will now work to understand what reduced CBFB means on the cellular level and how reduced CBFB leads to providing a completive advantage to cancerous cells. Further, he hopes to elucidate if that advantage can be countered by normalizing CBFB levels, and if reduced CBFB expression actually predisposed hematopoietic stem and progenitor cells to become leukemic, rather than just making them more fit after they become cancerous. His work suggests that the core binding factor pathway is an exciting new avenue for research into AML and may provide valuable ways to both treat and possibly prevent AML progression.