Targeting the HMGA1 Chromatin Regulator in MLL1-Rearranged Pediatric Leukemia

Dr. Linda Resar – Johns Hopkins University School of Medicine, Baltimore, MD

MLL-r leukemia is a highly aggressive and frequently lethal form of childhood leukemia for which new therapies are urgently needed. MLL-r leukemia is caused by an abnormal fusion protein, called MLL-r, which activates or “turns on” genes that cause normal blood cells to transform into aggressive leukemic cells (or blasts). While prior studies focused on developing drugs to block proteins that “partner” with MLL-r, this has not improved outcomes for most children. Here, we take a novel approach by focusing on the HMGA1 protein as a “molecular key” required in MLL-r leukemia. We discovered that HMGA1 is a potent oncogene (or cancer-causing gene) that transforms normal blood cells into leukemic blasts in experimental models. HMGA1 is also up-regulated in MLL-r leukemia, with highest levels in cells that survive chemotherapy. Our preliminary data suggests that HMGA1 “unlocks” regions of the genome to activate genes that allow leukemia cells to resist therapy. Using a gene editing approach called CRISPR, we found that inactivating HMGA1 prevents leukemic cells from surviving therapy, suggesting that therapies which block HMGA1 will be effective in MLL-r leukemia. To test this, we now propose: 1) genetic and biochemical studies to determine why HMGA1 is required for resistance to therapy in MLL-r leukemia, and, 2) to test drugs that disrupt HMGA1 function in MLL-r leukemia. This work promises to provide new treatment paradigms and improve outcomes for children with MLL-r leukemia.