PROJECT SUMMARY

Myelodysplastic syndrome (MDS) is a disorder in which the bone marrow is unable to make blood cells normally. Many different gene mutations are found in patients with MDS and understanding how these mutant genes alter blood cell development is critical to developing new treatments. Mutations in the gene Additional Sex Combs Like 1 (ASXL1) are common in MDS. Patients with ASXL1‐mutant MDS have decreased survival and are more likely to experience transformation to acute myeloid leukemia (AML), a feared and difficult to treat complication. We lack treatments that can specifically target ASXL1 mutations or decrease their propensity to drive transformation to AML. We have discovered a previously unappreciated role for ASXL1 in developing white blood cells. A protein called RNA polymerase is responsible for reading the genetic code from DNA and making a short‐term copy, called RNA, that instructs the cells to make specific proteins. As white blood cells develop and prepare to leave the bone marrow, ASXL1 slows down RNA polymerase, enabling them to develop normally. How this process is altered by mutations in ASXL1 is unknown. We will use the latest advances in single‐cell sequencing technology to understand how mutations in ASXL1 alter RNA polymerase function in cell lines and in cells from patients with MDS. We will generate the largest dataset to date of RNA polymerase binding in patients with MDS, which will enable us to understand whether mutations in ASXL1 change its activity. These studies will help us understand how ASXL1 mutations alter white blood cell development in patients with MDS. This understanding will enable us to develop better drugs that can potentially target mutant ASXL1, improving survival for MDS patients and preventing transformation to AML.