PROJECT SUMMARY

Mutations in the ASXL1 gene are among the most frequent genetic alterations in patients with myelodysplastic syndromes (MDS), a group of blood disorders that can lead to leukemia. These mutations are also seen in related cancers and in early disease stages. Recent research has shown that ASXL1 mutations enhance the activity of a protein complex called PR-DUB, which controls gene expression by removing histone H2A monoubiquitination. This change in activity is believed to contribute to disease development and may represent a promising therapeutic target. Despite this progress, we still do not fully understand how ASXL1 mutations alter the function of this protein complex or promote abnormal gene regulation. One key limitation is the lack of detailed structural and biochemical information of the wild-type and mutant forms of the complex. This project aims to define how ASXL1 mutations change the structure and behavior of the PR-DUB complex, determine how these changes affect chromatin regulation, and identify additional molecular factors involved in mutant ASXL1 function. Together, these studies will improve our understanding of MDS biology and could support the development of new, more effective therapies for patients with ASXL1 mutations.