PROJECT SUMMARY Myelodysplastic-syndrome (MDS) is a cancer of stem cells that form the blood. In MDS, abnormal stem cells accumulate but are unable to make enough functional blood cells, and can eventually transform to acute myeloid leukemia (AML). While we know that this slow transformation process starts with mutations in specific genes, we do not know why such MDS-mutation-bearing cells have a competitive advantage over normal cells. Understanding this process is fundamental to figuring out new ways to treat patients. We have assembled a team of researchers, unique models and cutting-edge technology to determine whether infectious challenge provides a selective environment for hematopoietic clones with mutation of MDS/AML-associated genes. We expect to determine at a single-cell level how MDS-genic mutations affect stem cell biology, and whether changes in the environment of the bone marrow help mutant stem cells generate disease.

NARRATIVE The proposed work focuses on determining whether infectious challenge provides a selective environment for hematopoietic clones expressing cancer-causing lesions, then maps both the marrow architecture and underlying single cell transcriptome and epigenetic changes to understand cellular competition and selection.