Project Term
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Project Summary
The cohesin and BAF complexes are both epigenetic regulators of dynamic chromatin accessibility. Recurrent mutations are observed in proteins of both complexes in adverse risk acute myeloid leukemia (AML). We will use Stag2 (cohesin) and Arid1a (BAF) knockout mice and AML cell lines to deconvolve their unique and cooperative roles in hematopoiesis. This proposal will test the hypothesis that their overlapping functions constitute viable therapeutic targets for these recalcitrant patients.
Lay Abstract
Hematopoietic stem cells are remarkable cells primarily found in the bone marrow, in the center of our bones. These unique cells have the power to generate all the different types of blood cells our bodies need throughout life. They can either make copies of themselves to stay as stem cells or mature into “differentiated cells” like red blood cells, white blood cells, or platelets. However, when these stem cells are exposed to certain types of stress, such as aging or DNA changes (mutations), the stem cells pool might exhaust or start working improperly, disrupting the balance of blood cell production and affecting overall health. This imbalance can lead to conditions like Myelodysplastic Syndrome (MDS) and, if it worsens, Acute Myeloid Leukemia (AML).
Our research aims to understand how specific mutations can drive these diseases, focusing on STAG2 and ARID1A functions. STAG2 plays a role in organizing DNA within cells to ensure that the right genes are active at the right time during blood cell development. Meanwhile, ARID1A is part of a protein group known as the BAF complex, which remodels DNA structure, either opening up regions for gene activation or closing off genes that should stay inactive. Mutations in either of these genes can disrupt normal blood cell development, and we’re particularly interested in understanding how STAG2 and ARID1A mutations might work together to influence these processes.
To explore this, we’ll use cell and mouse models to examine the unique and shared roles of these genes in blood formation. Our findings will be highly relevant for developing treatments, especially drugs that inhibit the BAF complex. These drugs may hold promise for patients with STAG2 mutations, which are commonly found in AML patients who do not respond well to current therapies.
Program
Grant Subprogram
