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Alternative RNA Splicing of CSF3R in Promoting Myelodysplastic Syndromes

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Virginia Commonwealth University Richmond United States

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More effective therapies for myelomdysplastic syndromes MDS can be developed if we know more about how the disease develops. One of the most exciting advances has been the identification of mutations in genes encoding splicing factors. These occur in 50-70 percent of all adult patients with MDS. These proteins acts as a machine to process instructions messenger RNA that lead to the production of a specific protein. 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. We are identifying that specific splicing factor and whether there is any required posttranslational modification of the splicing factor. This knowledge will inform us on how MDS begins and how to interrupt its development and progression to leukemia. Also, we have found that this defective receptor results in too much growth and too little differentiation. We have identified that splicing factors such as U2AF1 and post-translational modification involving phosphorylation contribute to processing of the message for the granulocyte colony stimulating factor receptor. SRSF2 may also play a role in regulating CSF3R. We are developing a mouse model that will allow us to describe in greater, more accurate detail the molecular changes and cell behaviors due to that defective receptor. Our work could allow us to screen for drugs that correct the MDS condition by correcting the faulty splicing and may advance the use of the receptor as a clinical laboratory tool.

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Technical Report,13 Dec 2017,12 Dec 2018



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