Mechanisms of oncogenic gene regulation by MYST-family acetyltransferases KAT6A and KAT7 in AML

Acute myeloid leukemia (AML) is an aggressive blood cancer occurring in both children and adults. Frequently, patients are treated with chemotherapy which can be followed by stem cell transplant. Only some patients are cured, and adverse effects remain a significant challenge. Therefore, intense research has focused on uncovering targeted, less toxic treatments, some of which have shown remarkable clinical results. Menin inhibitors (MIs) are an exemplar of targeted therapy recently approved for a subset of AML patients with genetic abnormalities of the MLL gene. In these patients, the resulting MLL fusion proteins over-activate leukemia genes by binding to chromatin, which consists of DNA packaged around proteins called histones. MLL fusions bind chromatin by interacting with another protein, called menin. MIs disrupt this interaction, displace MLL fusions from chromatin, and silence these genes. However, despite high rates of initial clinical response to MIs, leukemia still finds a way to escape therapy and ultimately comes back in many patients. It has recently been shown that inhibition of two proteins, called KAT6A and KAT7, can prevent the growth of leukemia resistant to MI. While we now know that KAT6A and KAT7 are potential targets which somehow cooperate with MLL fusions to promote leukemia, how exactly these proteins support malignant cells remains unclear. To answer this question, I will generate experimental leukemic cell models in which these two proteins can be rapidly degraded by treating cells with small molecules. The rapidity of degradation achieved in this way will enable me to study those cellular changes occurring immediately after leukemic cells lose KAT6A or KAT7. This will identify the processes directly affected by KAT6A or KAT7. Moreover, it will show how key genes fueling leukemic growth are promoted by KAT6A or KAT7. While I will initially conduct this work on cells harboring MLL fusions, these experiments will extend to models of NPM1-mutant leukemia, which comprises ~30% of adult AMLs, and which is also highly sensitive to MIs. Ultimately, these studies will reveal in detail how KAT6A and KAT7 support leukemogenic processes. This may inform clinicians how to use KAT6A and KAT7 inhibitors in the most efficient manner. Also, these studies have the potential to identify key molecular actors implicated in KAT6A and KAT7 functions, which may be therapeutically targeted in the future.