MYST acetyltransferases as a targetable dependency in JMML
Juvenile Myelomonocytic Leukemia (JMML) is a type of blood cancer that affects young children. Even with intensive treatment, the cancer often comes back. Mutations (changes) in a gene called SETBP1 increase the chances that this cancer will return. When there is a mutation in SETBP1 in the cancer, only 18% of children with JMML live for more than five years after treatment. Despite how important SETBP1 is in JMML, we have no drugs that target changes in this gene to improve survival for children with this cancer. To develop therapies targeting SETBP1, we need to learn more about how changes in this gene cause blood cancer. We know that SETBP1 turns on genes that cause leukemia, but how it does this is not well understood. Our lab recently discovered a group of proteins that are important in leukemias with SETBP1 mutations. This gives us an opportunity to learn how changes to the SETBP1 gene lead to blood cancer and to design treatments that reverse those effects.
Project Goals
Our overall goal is to create new drugs that increase the survival of children with JMML. Using mouse models, we found that inhibitors of MYST proteins are highly effective against JMML with SETBP1 mutations. The first goal of this proposal is to understand how MYST proteins help SETBP1 drive difficult-to-treat leukemias. The second goal of this proposal is to test drugs that target MYST proteins against human leukemia samples. Acheiving these goals will shed light on precisely how SETBP1 gene mutations turn on other genes to make leukemia hard to treat. We will also establish MYST proteins as a new drug target in JMML. Drugs that target MYST proteins are in the final stages of clinical trials for breast cancer. This will allow us to quickly pivot to testing MYST inhibitors for children with JMML. We will work closely with Drs. Tasian and Stieglitz—doctors and experts in the JMML field—to ensure that these drugs make it to patients as rapidly as possible.
