Childhood Cancer

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Mutagenesis and disease progression in RUNX1 mutant blood stem cells is caused by inflammation-induced hyperactive signaling and supraphysiological mitochondrial ROS

St. Jude Children’s Research Hospital
Dirk Loeffler, PhD
Grant Type: 
RUNX1 Early Career Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Leukemia, Acute Myeloid Leukemia (AML)
Project Description: 

Familial platelet disorders with a predisposition to acute myeloid leukemia (FPD/AML) is an inherited disease caused by mutations encoding for the RUNX1 gene. RUNX1 is an important regulator of blood cell formation and is often mutated in blood diseases. Individuals with FPD/AML have bleeding disorders, a low number of platelets, platelet defects, and very often develop leukemias or related blood disorders early in life. RUNX1 mutations have been associated with defects in blood cell formation, expansion of blood stem cells, and DNA repair. However, RUNX1 mutations alone are not sufficient for leukemia development and disease progression requires additional currently unknown factors and mutations. How these mutations are acquired and why some FPD/AML patients remain disease-free while others develop leukemia early in life is completely unknown. Our research attempts to close this knowledge gap and suggests that disease progression of FPD/AML is driven by certain inflammatory signals. Our preliminary data suggest that RUNX1 mutant HSCs are hypersensitive and/or hyperactive when exposed to inflammation. Insights obtained in our research could thus lead to novel strategies to manage inflammation and prevent disease progression in FPD/AML patients.

Project Goals:

The goal of this project is to investigate how inflammation contributes to disease progression in individuals with FPD/AML. RUNX1 mutations in FPD/AML have been associated with defects in blood cell formation, expansion of blood stem cells, and DNA repair, but the molecular mechanisms contributing to disease progression remain poorly understood. Insights into FPD/AML are currently derived from decade-old molecular and cell biology tools and the study of mixed cell populations. While mixtures of cell populations are easy to work with, the properties of individual cells are blended together and often lost. Analyzing mixed cell populations is thus comparable to studying a smoothie instead of its ingredients. Important information about the fundamental properties of individual cells and their contributions to disease progression is not accessible using these tools. To overcome these limitations, I develop novel advanced microscopy techniques that can measure individual cell behaviors over time and avoid the shortcomings of earlier studies. Using these tools, our goal is to understand how inflammation affects individual cells with RUNX1 mutations. Studying the effects of inflammation on individual cells instead of mixed populations will allow us to identify the cells (‘ingredients’) that contribute to disease progression and the factors driving this process. Insights derived from individual cells will help us to devise new strategies to devise novel and better strategies to prevent disease progression in FPD/AML patients.

Co-funded by: 
The RUNX1 Research Program