Grant: CIHR Fellowship

Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow, which originate from mutations in cells in the marrow called stem cells. Mutated stem cells do not mature into functional cells, which results in reduced numbers of red cells, white cells and platelets circulating in the blood. As the disease progresses, the bone marrow may completely fail to produce normal cells, or may transform into a cancer such as acute myeloid leukemia. It is not understood why stem cells become defective in MDS, but MDS cells often have chromosomal abnormalities. The most common abnormality, the loss of part of chromosome 5, is a key feature of the MDS subtype called 5q- syndrome. The commonly-deleted region of chromosome 5q harbors several genes, which when lost results in MDS. At the present time, there are no curative therapies for 5q- MDS, although a drug called lenalidomide relieves some symptoms. Good mouse models of MDS are crucial to design improved drug therapies. Thus, the objective of this research project is to establish a mouse model of MDS based on the most common gene deletions seen 5q- syndrome, with the goals of studying how lenalidomide works. We hypothesize that the deletion of three specific genes present in the commonly-deleted region on chromosome 5q results in the symptoms of MDS. Therefore, we will reduce expression of these genes in human stem cells, and determine whether mice injected with these stem cells develop symptoms of MDS. The genes are the RPS14 gene, which is thought to be responsible for the loss of red cells, and two microRNA genes, which we speculate may allow abnormal stem cells to survive and outcompete the normal cells in the marrow. We hypothesize that lenalidomide works by increasing the expression of one or more of these genes, and we will determine if this is true using our mice. Our model for MDS will provide molecular insight into the disease, and should permit the development and/or evaluation of novel therapies.