Elucidating HMGA1 Pathways to Target in Therapy for Refractory MLL-rearranged Pediatric Leukemia
Mentor: Linda Resar
The primary goal of this project is to investigate the mechanism through which HMGA1 induces deregulated cell growth and immune escape, both of which are characteristic of pediatric mixed-lineage leukemia rearranged (MLL-r) acute leukemia. MLL-r acute childhood leukemia is a refractory cancer in infants and children due to its resistance to therapies. While other groups have identified many proteins that abnormally fuse with MLL to form the rearrangement, these findings have not generated improved therapies. Thus, there is an unmet need to study the molecular mechanisms underpinning resistance of MLL-r acute leukemia, which could ultimately contribute to the development of new therapies. Focusing on HMGA1 could address this problem. Adding to the well-established correlation between HMGA1 overexpression and relapse in childhood leukemia, preliminary studies from Dr. Resar’s lab confirmed that HMGA1 is up-regulated in MLL-r leukemia. As one component of architectural transcriptional factors, HMGA1 induces stem cell properties by upregulating genes associated with proliferation and pluripotency. For example, essential developmental pathways like Wnt signaling are reported to be amplified by HMGA1. These pathways could foster cell growth. The Resar lab discovered that blocking HMGA1 expression disrupts diverse cancer phenotypes. Given the function of HMGA1 in regulating cell growth and promoting therapy resistance, we hypothesize that 1) HMGA1 drives a highly plastic, stem-like phenotype in MLL-r leukemia by inducing transcriptional networks involved in stem cell function and therapy resistance. 2) Targeting HMGA1 in MLL-r leukemia will be effective therapeutically. 3) HMGA1 recruits active histone marks to activate genes involved in refractory disease and stem cell properties. To test these hypotheses, we propose the following aims: 1) To assess HMGA1 gene expression in primary patient samples through qRT-PCR. 2) To identify pathways up regulated by HMGA1 using Ingenuity Pathway Analysis. 3) To identify potential drugs to target HMGA1 pathways using connectivity mapping. My hope is that this research will lead to novel therapies for childhood acute myeloid leukemia.