Identification and Characterization of Pathways Dysregulated by MMSET E1099K Mutation in Relapsed Pediatric Acute Lymphoblastic Leukemia and Their Role in Drug Resistance
While the outcomes for childhood leukemia have improved dramatically over the last four decades, the prognosis for children who relapse is poor. Relapsed leukemia, therefore, remains one of the main causes of deaths related to pediatric cancer. Discovering the underlying pathways that lead to resistance to chemotherapy and relapsed disease is a top priority to improve outcomes for these patients. To prevent relapse and improve treatment response, our laboratory has focused on discovering genetic mutations responsible for disease recurrence and chemotherapy resistance. Mutations in a gene known as MMSET have been identified as one of the most common mutations in relapsed leukemia in children. This mutation in other cancers universally imparts a poor prognosis suggesting that this mutation has a role in drug resistance.
We have developed leukemia cell lines with and without the MMSET mutation and will expose the lines to chemotherapeutic agents commonly used in the treatment of pediatric leukemia to test this theory. Furthermore, we plan to identify the pathways controlled by the MMSET mutation and identify the genes that are activated by these pathways allowing us to further understand the drug-resistant cells' characteristics. We will validate these findings in mice using both our cell lines and paired diagnosis/relapse patient samples obtained from the Children's Oncology Group (COG) bank. Our long-term goal is to use this information to develop novel, targeted therapy to prevent the emergence of resistant cancer cells and to restore sensitivity to chemotherapy.
Project Update 2020
While we have improved the outcomes for children with newly-diagnosed pediatric leukemia drastically in the last 50 years, the prognosis for children who relapse remains poor. To prevent relapse and improve the way children respond to treatment, my research focuses on a mutation in a gene called MMSET that is commonly seen in relapsed pediatric leukemia and plays a role in how the cancer cell’s genes are controlled. By understanding the effects of this mutation, we can improve therapy and outcomes for these children and possibly prevent relapse from occurring. Our results to date indicate that mutations in the MMSET gene operate collaboratively with other leukemia-specific alterations to evade the effects of chemotherapy. This information is shedding light on the role MMSET mutations play on gene expression in pediatric leukemia and is helping us understand the reason this cancer does not respond to therapy and leads to relapsed disease. This information will help researchers develop a novel treatment to improve outcome for patients harboring this mutation.