Histone methyltransferases as key dependencies in SETBP1-mutant leukemias

Mutations in a gene called SET Binding Protein 1 (SETBP1) are frequently found in several blood cancers, such as atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and chronic neutrophilic leukemia (CNL). These mutations are linked to worse outcomes for patients, such as lower survival rates and a higher risk of cancer recurrence. This is because when SETBP1 is mutated, it causes certain blood cells to grow uncontrollably and become cancerous. Unfortunately, no drugs specifically target mutant SETBP1, and no tailored therapies exist to treat these mutations. To improve the survival of patients with SETBP1 mutations, we need to understand better how SETBP1 mutations cause blood cancer. We have recently discovered several proteins that work together with SETBP1. These proteins, called histone methyltransferases, turn other genes on and off.  Under normal conditions, these methyltransferases add chemical tags to DNA and histones (proteins that DNA wraps around). These tags turn genes on and off to regulate cell growth. However, in leukemia this process is disrupted, resulting in the uncontrolled growth of cells.

Based on our discovery that methyltransferases work together with mutant SETBP1, my first goal for this project is to study how these proteins interact in SETBP1 mutant cells. I will determine whether these proteins form a large complex with mutant SETBP1 or if they interact with mutant SETBP1 in multiple smaller separate complexes. This will increase our understanding of how SETBP1 controls these methyltransferases. Next, I will explore how mutant SETBP1 impacts the binding of methyltransferases to DNA and their ability to add chemical tags to histones. By studying these changes, I aim to understand how these modifications impact gene activity to cause leukemia. Finally, I will evaluate the functional importance of these methyltransferase complexes by testing whether drugs that inhibit them can slow down cell growth and correct gene activity in cells harboring SETBP1 mutations. 

There is a critical need to understand how mutant SETBP1 affects methyltransferases and gene activity ultimately contributing to blood cancer. My research could reveal new therapeutic targets, provide insights into how these mutations lead to leukemia, and improve our understanding of SETBP1-mutant leukemias to develop improved therapies for cancers driven by SETBP1 mutations.