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Pharmacologic Enhancement of Residual Wild Type RUNX1 Protein Activity in FPD/AML

Boston Children’s Hospital
Alan Cantor, MD, PhD
Grant Type: 
RARE Grant Program (Research Accelerating RUNX1 Exploration)
Year Awarded: 
Type of Childhood Cancer: 
Acute Myeloid Leukemia (AML)
Project Description: 


Familial RUNX1 disorders [familial platelet disorder (FPD)/ acute myeloid leukemia (AML)] are caused by inherited mutations in one of the two copies of the RUNX1 gene. The RUNX1 gene produces a protein that normally turns on and off other key genes required for normal blood cell development. Individuals with FPD/AML have low platelet counts and increased leukemia risk. Because the leukemia onset takes time, there is a window of opportunity to intervene to prevent leukemia development.

Project Goal

The objective of this proposal is to identify drugs that increase the activity of the remaining good RUNX1 gene copy in order to prevent leukemia development. The RUNX1 protein has several mechanisms that normally dampen its full activity. In prior work, we discovered a chemical modification that controls one of these mechanisms and identified an FDA-approved drug that reverses this inhibitory effect. The aim of this proposal is to test this drug and related compounds collaboratively in FPD/AML patient cells and an FPD/AML mouse model. We will also screen up to 100,000 bioactive compounds through the Harvard Medical School Institute of Chemical and Cellular Biology for additional molecules that activate residual RUNX1.

The successful completion of this study will be the identification of drugs, and/or lead compounds, that enhance residual RUNX1 protein activity in an FPD/AML setting. These would be developed to prevent leukemia development in FPD/AML patients. Positive results have the potential for rapid clinical translation since one of the compounds we identified in preliminary studies is an oral FDA-approved drug that is well tolerated and in current clinical use.

Co-funded by: 
The RUNX1 Research Program