Alternative RNA Splicing of CSF3R in Promoting Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are increasing in incidence, as the population ages. Despite recent drug approvals of lenalidomide and hypomethylating agents for MDS, the prognosis for someone with MDS is fair to poor. More effective therapies can be developed if we learn more about how the disease develops. One of the most exciting advances has been the identification of mutations in genes encoding splicing factors. These mutations occur in up to 85% of all patients with MDS, and they are not found in patients with related blood diseases, like acute myeloid leukemia. The genes encode components of the splicing machine. This group of proteins acts as a team to process the instructions (messenger RNA) that lead to the production of a specific protein. Investigators have thought that splicing factor mutations produce defective proteins that lead to defective cell behaviors (like cell division or maturation) that result in defective white blood cell production. However, we know next to nothing about the splicing targets and how mutations alter specific cell behaviors. We have identified that the receptor for the most important growth factor for the production of granulocytes (the white blood cells most affected in MDS, is subject to splicing. These splicing changes result in a defective receptor, which fails to instruct blood cells to mature. We have developed a test to identify which specific splicing factor is involved in processing the messenger RNA for this receptor. Our proposal will identify that splicing factor and allow us to determine how to interrupt its defective splicing. Also, we have identified that this defective receptor results in too much growth and too little differentiation. We will develop a mouse model that will allow us to describe in greater, more accurate detail the molecular changes and cell behaviors due to the defective receptor. Our work will also allow us to screen for drugs that will correct the MDS condition by correcting the faulty splicing.