Identification and Characterization of Pathways Dysregulated by MMSET E1099K Mutation in Relapsed Pediatric Acute Lymphoblastic Leukemia and Their Role in Drug Resistance
Background: 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.
Project Goal: 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 2021: The research funded by my Alex's Lemonade Stand Young Investigator's Grant has shed light on how this mutation plays a role in drug resistance and relapse. Interestingly, we found that the NSD2 mutation does not directly lead to drug resistance or affect the way the cancer cells grow in a uniform manner, but the impact of the mutation is dependent on the underlying cellular pathways in each cancer cell line. This is unique to this mutation as there is usually a consistent means by which the mutations lead to uncurable disease. Genetic sequencing has revealed a genetic and epigenetic signature unique to the cancer cells containing this mutation and has helped us understand how this mutations leads to drug resistance and relapse. With our better understanding of how this cancer does not respond to therapy and leads to relapsed disease, we hope to find ways to target therapy to help improve outcomes for patients with this mutation in the future.
