Delineating the Epigenetic Landscape and Pro-Inflammatory Gene Expression Program Associated with RUNX1 Familial Platelet Disorder


IN PARTNERSHIP WITH RUNX1 RESEARCH PROGRAM (2021-PRESENT)

Lucy Godley MD, PhD, University of Chicago

One of the first genetic disorders to be identified with an increased risk for developing cancers was discovered as inherited mutations in the gene RUNX1, which encodes a master regulator of blood cell development. Individuals with inherited RUNX1 mutations have familial platelet disorder (RUNX1-FPD) and suffer from a variety of life-long medical issues including low platelets counts, which leads to bleeding and wound healing problems, and inflammatory conditions such as arthritis, allergies, and eczema. Notably, they also have an increased risk of developing a variety of blood cancers, which is driven by gaining additional DNA mutations in hematopoietic stem and progenitor cells (HSPCs) with age, a process referred to as clonal hematopoiesis (CH). It is now appreciated that inflammation contributes to the expansion of these mutated clones, and those with RUNX1-FPD have high levels of systemic inflammation. However, the cause of this increased inflammation and it how promotes CH and eventually to cancer is incompletely understood. Here, Lucy Godley and her group will test the idea that the elevated inflammation characteristic of inherited RUNX1-mutations is due in part to altered epigenetic organization in stromal cells in the bone marrow that leads to pro-inflammatory gene expression.

The team has a significant number of samples from patients with RUNX1-FPD from which they will isolate T and B cells, as well as mesenchymal stromal cells (MSCs). Using the lymphocytes, they will examine the epigenetic marks and gene expression patterns to detect signatures of pro-inflammatory signaling when compared to wild-type cells. They will then test how these cells behave when they are placed into contact with MSCs in the presence of agents designed to mimic elevated systemic inflammation. Finally, they will profile drugs to test their ability to abrogate the pro-inflammatory gene expression program. These studies will reveal the epigenetic modifications that accompany the proinflammatory gene expression programs associated with RUNX1-FPD in MSCs and lymphocytes, and whether drug treatments can normalize gene expression and lower the inflammatory milieu. This approach could ultimately lead to a clinical trials of RUNX1-FPD patients to slow or even prevent progression of clonal hematopoiesis, thus reducing leukemia risk.

 

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