Childhood Cancer

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Therapeutic targeting of clonal hematopoiesis in RUNX1 mutant FPDMM

University of Pennsylvania
Robert Bowman, Ph.D.
Grant Type: 
RARE Grant Program (Research Accelerating RUNX1 Exploration)
Year Awarded: 
Type of Childhood Cancer: 
Leukemia, Acute Myeloid Leukemia (AML), Juvenile Myelomonocytic Leukemia (JMML)
Project Description: 

In families with an inherited condition called familial platelet disorder, patients are often at risk for developing life-threatening myeloid leukemias. This disorder is characterized by mutations in certain genes, specifically in RUNX1. People with these mutations may experience disruptions in normal platelet function, experience high inflammation, and face a significant risk of developing leukemia. The onset of leukemia in FPDMM is preceded by a phenomenon called clonal hematopoiesis, where certain cells in the blood acquire mutations, giving them a growth advantage in the bone marrow. Our overall goal is to find specific genes or drugs that can target these mutant cells with RUNX1 mutations and additional mutations related to clonal hematopoiesis and leukemia. The most common of these second-site mutations occurs in a gene called BCOR. Our early findings indicate that when RUNX1 mutations are combined with mutations in BCOR, it leads to changes in the regulation of a group of genes called the HoxA family. These genes seem to rely on a regulatory partner called Menin. We believe that suppressing the activity of Menin can help control the abnormal growth of cells with RUNX1 and Bcor mutations, ultimately reducing the risk of clonal expansion. We plan to test this through experiments in the lab and by studying how cells respond to treatment.

Project Goal

The goal of this grant is to evaluate new therapies that can target cells with preleukemic mutations, and prevent them from ever turning into leukemia. We believe that there is a specific enzyme, Menin, responsible for making these mutant cells more fit than their neighbors, and therapeutic targeting of this enzyme can eliminate these preleukemic cells. In addition to targeting Menin, we will test a wide range of potential drug targets using chemicals and genetic approaches to find new candidates. Our overall goal is to identify therapies that can prevent a FPD patient from developing leukemia.


Co-funded by: 
The RUNX1 Research Program