Precision Medicine For DNMT3A-Mutant T-cell ALL
Grant Challen
PhDWashington University in St. Louis
Project Term: July 1, 2022 - June 30, 2025
T-cell ALL is an aggressive blood cancer with poor overall survival, high relapse rates, and significant treatment-related side effects. Using primary T-ALL patient samples, this project will study the importance of JAK/STAT signaling and the gene BIRC5 in the pathology of T-ALL driven by DNMT3A mutations using genetic and pharmacological tools. The goal of this proposal is to develop precision medicine approaches for DNMT3A-mutant adult T-ALL patients, a group with poor clinical outcomes
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of acute leukemia that affects a particular a type of white blood cell called T lymphocytes. Compared to the more common B-cell ALL, T-ALL cases have a poor prognosis, mostly due to toxicities associated with high-dose chemotherapy and increased risk of disease relapse. Thus, new treatments for T-ALL patients based on their individual genetic profile are urgently needed. Genome sequencing studies of T-ALL patients have identified virtually all of the important genetic mutations that drive this blood cancer, including the gene DNMT3A which is mutated in 10-18% of these patients. While DNMT3A is also mutated in other types of blood cancer, the specific pattern of mutations in T-ALL patients is distinct and suggests it may have a different function in this subtype of leukemia. We recently demonstrated using mouse genetic models that Dnmt3a acts as a T-ALL tumor suppressor. T-cells lacking Dnmt3a are more susceptible to T-ALL transformation when exposed to another T-ALL oncogene called NOTCH1. In T-ALL patients, DNMT3A mutations frequently co-occur with NOTCH1 mutations and predict poor clinical outcome and chemotherapy resistance. As the next step, we have now analyzed tumor cells from T-ALL patients. We find T-ALL patient cells with DNMT3A mutations are harder to kill than other types of T-ALL, and are resistant to the normal types of chemotherapy used to treat these patients. To understand the reasons for this, we analyzed the gene expression profile of these patient cells and found that DNMT3A mutations increased activity of a signaling pathway called JAK/STAT. When DNMT3A mutant T-ALL cells were treated with a JAK/STAT inhibitor, they became sensitive to chemotherapy again. When the types of JAK/STAT genes responsible for this were analyzed, a gene called BIRC5 was dramatically increased in DNMT3A mutant patient cells. BIRC5 encodes for a protein that enhances the survival of cells under stress. We then treated patient cells with a BIRC5 inhibitor and showed DNMT3A mutant patient cells were sensitive, whereas other types of T-ALL were unaffected. Therefore, we propose that BIRC5 is specifically required for the survival of DNMT3A mutant T-ALL cells. The goal of this application is to comprehensively analyze the function of BIRC5 in T-ALL, with the goal of using BIRC5 inhibition as precision medicine for these DNMT3A mutant T-ALL patients. In the first part of the project, we will inhibit BIRC5 in T-ALL patient cells using both genetic and pharmacological tools and examine the effect on cell survival and leukemia development. In the second part we will use cellular and biochemical methods to identify the unique roles of BIRC5 in DNMT3A mutant T-ALL cells. This information will help us design better drugs to inhibit BIRC5. Our goal is to identify new therapies for T-ALL patients with DNMT3A mutations who have increased risk of treatment failure and disease relapse.