Project Term
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NYU Grossman School of Medicine
New York, NY
United States
Project Summary
Mutations in the ASXL1 gene, among the most common in leukemia patients, lead to the production of abnormal proteins that disrupt the normal function of BAP1, an enzyme that regulates how genes are turned on and off in cells. This project will apply structural, biochemical, and genomic approaches to determine how these mutations alter the ASXL1–BAP1 complex and interfere with normal gene regulation. The findings will advance our understanding of how ASXL1 mutations drive leukemia and guide the development of new targeted therapies.
Lay Abstract
Mutations in the gene ASXL1 are very common in patients with blood cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent studies to understand the impact of ASXL1 mutations on the function of ASXL1 protein have identified that ASXL1 mutations create an abnormal form of ASXL1 protein that has a new function. Specifically, ASXL1 is normally part of a multi-protein enzyme machinery called the Polycomb Repressive Deubiquitinase Complex (PR-DUB). Several groups have now found that leukemia-associated mutations in ASXL1 incorporate into the PR-DUB complex and hyperactivate the enzymatic activity of the complex. This is an exciting discovery as changes in enzyme function in cells often signify an attractive target for drug development. Having a therapeutic selective for ASXL1 mutations could be a major advance for patients with ASXL1-mutant leukemia, given the high frequency and poor clinical outcomes associated with these mutations.
Despite the above insights into the impact of ASXL1 mutations in leukemia, we currently do not know how exactly ASXL1 mutations alter or promote the function of the PR-DUB complex. This limitation is due in part to the fact that we do not yet have molecular structures of the mutant ASXL1 containing PR-DUB complex. Having this information will be very important in enabling future therapeutic discovery efforts to identify drugs which interrupt the activity of mutant ASXL1.
In this proposal, we have assembled a team of scientists and physicians with complimentary and non-overlapping expertise in structural biology of the PR-DUB complex (Dr. Karim-Jean Armache, NYU) and the molecular and clinical biology of leukemia and ASXL1 (Dr. Omar Abdel-Wahab, MSK). Both investigators are based in the New York City area and have an established collaboration on understanding how ASXL1 mutations alter ASXL1 function.
In Aim 1, we will create the first high resolution structures of the wild-type and mutant forms of ASXL1 in complex with other proteins in PR-DUB, including their interactions with histone proteins that package DNA. If successful, these structures will provide the first detailed visualization of leukemia-associated ASXL1 mutations.
In Aim 2, we will identify the specific functions of each domain in ASXL1 and determine how leukemia-associated mutations perturb their molecular function.
In Aim 3, we will analyze leukemia cells carrying ASXL1 mutations to identify additional genes and pathways that cooperate with this abnormal activity to drive disease progression.
Overall, this proposal will provide new fundamental biological insights into this frequently mutated protein in leukemia. The knowledge gained will directly inform the design of next-generation therapies that specifically target mutant ASXL1 or its aberrant complexes, offering new avenues for intervention in patients with limited treatment options.
Program