Defining epigenetic vulnerabilities in clonal expansions of RUNX1-FPD patients
Clonal hematopoiesis (CH) occurs when certain blood cells begin to grow abnormally and dominate over others, even in people who are otherwise healthy. This condition becomes more common with age and increases the risk of developing blood cancers. However, for individuals with a rare inherited disorder called RUNX1 familial platelet disorder (RUNX1-FPD), CH can appear at a much younger age. While these early clones are often unstable and less likely to lead to cancer, stable clones become more frequent as patients grow older, increasing their cancer risk.
Early detection of CH offers a crucial chance to intervene before the condition progresses to cancer. The challenge lies in identifying specific features of the abnormal blood cells to develop therapies that target only the problematic cells while sparing healthy ones. Patients with RUNX1-FPD have a mix of inherited mutated cells and additional mutated cells that drive CH, with the latter being a smaller fraction of the blood cells. These additional mutations often affect genes that control how DNA is packaged and read, but how these mutations contribute to the growth of abnormal clones is not well understood.
Project Goal
The goal of the study is to identify and target the abnormal blood cell clones driving CH in RUNX1-FPD patients before they progress to cancer. A major challenge is distinguishing between cells with inherited RUNX1 mutations and those with additional harmful mutations that drive the abnormal growth. To overcome this, the research will use an advanced technology called GoT-ChA, which can pinpoint genetic and epigenetic changes in individual cells from patient samples. This tool enables researchers to study how abnormal clones evolve and grow, using the healthy cells from the same patient as a comparison.
The study has two main objectives:
1) Understand how abnormal clones grow and change over time: Using GoT-ChA, researchers will analyze patient blood samples to map the evolution of abnormal clones and understand how specific mutations affect blood cell development.
2) Identify unique features of abnormal clones and test therapies: By studying how these clones differ from healthy cells, the project aims to discover specific features or pathways that can be targeted with therapies. Patient-derived stem cells will be used to test potential treatments, focusing on selectively eliminating harmful clones while preserving healthy cells.
Ultimately, this research will provide the foundation for new treatments to prevent blood cancers in RUNX1-FPD patients, offering hope for early interventions that improve long-term health outcomes.
