PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are bone marrow disorders characterized by insufficient production of healthy blood cells. ASXL1 mutations occur in ~15–20% of patients and are linked to poor survival and progression to acute myeloid leukemia, particularly truncating mutations that remove the protein’s C-terminus. ASXL1 regulates gene expression through the PR-DUB complex, which removes ubiquitin from histones. Truncation disrupts this control: the mutant protein still assembles into PR-DUB but makes it hyperactive and alters interactions with chromatin regulators, driving aberrant gene expression and impaired hematopoiesis. This gain-of-function suggests therapeutic opportunities.

To address this problem, we have assembled a collaborative team with expertise in structural biology, epigenetics, and leukemia biology. Together, we aim to understand how ASXL1 mutations change the structure and function of this complex, how they alter gene regulation across the genome, and which vulnerabilities can be targeted for treatment. Our preliminary studies show that truncated ASXL1 increases PR-DUB activity on chromatin. We will combine structural, genomic, and genetic approaches to define how ASXL1 mutations alter complex architecture, reshape the interactome and gene regulation, and identify therapeutic vulnerabilities. This work will provide new insight into how ASXL1 mutations drive MDS and help guide targeted treatments.