Clonal Hematopoiesis (CH) occurs when single mutational event multiplies in cells, and create different types of disease. We have learned that CH precedes myelodysplastic syndromes (MDS); however, even though >10% of patients over the age of 60 years have CH, only a very small fraction of these individuals progress to MDS, so determining which of these mutations truly is ‘premalignant’ is important.

About half of CH is in one gene: DNMT3A. The essential changes that the DNMT3A protein normally makes are due to a chemical process called “methylation.” We can now measure methylation throughout the billions of base pairs that make up the human genome, and study how the methylation process is hijacked to direct rogue growth of proteins. To compare methylation pattern in different DNMT3A mutants, we will use serially collected patient samples to measure how CH develops in people over time. The first part of the proposal is designed to discover which DNMT3A mutations carry the highest risk by virtue of how they interfere with normal gene methylation.

For the DNMT3A mutations that have methylation patterns that lead to MDS, we propose to remove them with gene therapy. We have developed a type of gene therapy called ‘clonoreversion’ which we have shown we can reduce levels of mutations in patient samples. To translate this faster to the clinic, we will use nanotechnology to package the gene therapy into a lipid bubble that will travel directly to the blood stem cells.