Marshall S. Horwitz, M.D., Ph.D.
2022 Funding recipient
Life History of MDS in Females: From Embryogenesis to Adult
Discovery Research Grant 2022
The goal of our research is to understand the origins and classification of MDS in order to improve treatment outcomes. To do so, we will analyze patient samples, using a new approach for extracting information about each blood cell’s history of cell divisions. Our analysis method is based on using acquired changes in the DNA of patients. Every time a cell divides, mutations occur. Each subsequent cell division passes on the prior mutations, along with new mutations, to its descendants, such that the errors in the genome record a history of a cell’s ancestry. In essence, each cell acquires its own unique “barcode” that allows its lineage to be recorded, similar to a family tree.
Using this approach, we will evaluate how MDS cells have grown and divided. The method for identifying the mutations is new and is based solely on the sequencing of mRNA at a single cell level. This greatly simplifies the process for identifying cell type and determining their ancestry.
We will study patients with different categories of MDS. A specific requirement, however, is the use of female subjects. The reason for this is that females contain two X-chromosomes, and one X-chromosome is inactivated randomly during development. The process of X-chromosome inactivation provides an independent check on the ancestry of cells and has previously been used to track the evolution of leukemia. In fact, the study of X-chromosome inactivation provided the first evidence that cancer originates from a single cell.