Elucidating HMGA Pathways to Target in Therapy for Refractory Pediatric Leukemia
The goal of my ALSF POST project is to investigate the role of High Mobility Group A (HMGA) chromatin remodeling proteins in pediatric leukemia. Both HMGA1/2 genes are highly expressed in embryonic stem cells during development and in adult stem cells where they maintain developmental potency and tissue homeostasis. In contrast, high expression of HMGA genes is hijacked in high-grade, malignant tumors with poor outcomes. In this setting, HMGA genes drive stem cell properties that help cancer cells spread and escape therapy. Although, the precise pathways regulated by HMGA genes in pediatric leukemia are just beginning to emerge. Over the past summer, I had the opportunity to investigate genes regulated by HMGA2 in a sarcoma model. I found that HMGA2 induces genes diverse transcriptional networks involved in tumor initiation and progression, including: 1) cell division (DNA replication, recombination and repair), 2) metabolism (carbohydrate and lipid) and 3) cancer (cell death and survival).
This summer, I will test the hypothesis that these pathways are disrupted by HMGA1 or HMGA2 in aggressive childhood leukemia. I will investigate both relapsed acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Relapsed ALL remains the leading cause of death in children with cancer. AML is important because only 50% of children with this disease achieve lasting remissions with standard therapy. I will use gene expression studies and assess the function of HMGA genes in leukemia using both cell-based and murine models. My hope is that focusing on the connection between leukemia and HMGA will lead to the discovery of new targetable pathways for the treatment of children with these diseases.
Mentored by Dr. Linda Smith Resar
Johns Hopkins University School of Medicine, Baltimore, MD