MDS with mutations in TP53 and “complex karyotype” is the highest risk category, with overall survival measured in months. This type of MDS is characterized by changes in the chromosome complement of the cell. These chromosome changes result in losses or gains of genes which contribute to disease. Unfortunately, we know very little about how this type of MDS arises and which genes contribute to its progression. We have developed a preclinical model and found that deletion of a piece of chromosome 5 causes the loss of genes which promotes this disease. The goal of this project is to use this model to find out how MDS with complex karyotype arises and which genes on chromosome 5 contribute to disease progression. This knowledge can help us identify specific treatments that kill cells with chromosomal changes which would be curative in this aggressive MDS.