Mentor Name: Linda Resar

Unfortunately, leukemia remains a leading cause of death in children with cancer. Childhood leukemias are comprised of two major subtypes, including: 1) acute lymphoblastic leukemia (ALL), and 2) acute myeloid leukemia (AML). Pediatric leukemias are frequently triggered by gene mutations that cause blood cells to grow in an uncontrolled fashion. The mutations also disrupt normal differentiation, leading to leukemia blasts with features of stem cells rather than mature blood cells. The stem cell features endow the leukemic cells with the ability to resist treatment, which is associated with relapse and poor outcomes in children. One form of childhood AML, called KMT2A-r AML, is caused by a fusion of the KMT2A gene (formerly MLL1) to another gene, which is denoted the KMT2A fusion or KMT2A-rearrangement (KMT2A-r). KMT2A-r AML is prevalent in infants and children and is associated with therapy resistance. Thus, there is an important need to better understand these abnormal gene fusions and why they make childhood leukemia resistant to therapy and highly lethal. Our research team focuses on the High Mobility Group A1 (HMGA1) chromatin regulator in pediatric leukemia. We discovered that diverse gene mutations associated with relapse converge on HMGA1, which allows the leukemic cells to resist therapy and behave in an aggressive fashion. We are now pursuing studies to uncover pathways used by therapy-resistant leukemia cells with the goal of designing effective therapies for children with this aggressive disease. The goals of this project are: 1) to investigate the role of HMGA1 in mediating therapy resistance in KMT2A-r AML, and 2) to develop new approaches to treat therapy resistant leukemia. We will focus on resistance to menin, a recently approved therapy for KMT2A-r AML because HMGA1 was recently identified among the gene signature of menin resistance in KMT2A-r AML.