HMG-I/Y in Pediatric Leukemia and Lymphoma

Background
Leukemia and lymphoma are the most common cancers afflicting children worldwide with over 5,000 cases each year in the United States alone. Leukemia is cancer of the white blood cells and lymphoma is a cancer involving the lymph tissue. Although major strides have been made in the treatment of these cancers, about 15% of children diagnosed with leukemia or lymphoma will relapse each year with abysmal clinical outcomes. Why some children develop refractory cancer and succumb to their disease is still not known. Moreover, therapy for these common childhood cancers is largely nonspecific, highly toxic, and associated with significant long-term side effects, such as heart disease, obesity, and diabetes. Thus, research is urgently needed to identify children at risk for more aggressive disease and to develop more rational and effective therapies.

Project Goal
With support from Alex’s Lemonade Stand Foundation (ALSF), we studied genes that contribute to the development of childhood leukemia and lymphoma with the long-term goal of designing better therapies. Our focus has been the high mobility group A1 gene (HMGA1, formerly called HMG-I/Y), which is expressed at high levels in leukemia and lymphoma. This gene is responsible for making proteins, called high mobility group A1 (HMGA1) proteins, that function by promoting cell growth during normal development before birth. This gene becomes activated in childhood cancers, leading to high levels of HMGA1 proteins and uncontrolled growth in cancer cells. HMGA1 proteins also endow cancer cells with stem cell properties that enable the cells to alter their growth patterns and behavior depending upon outside signals. While these properties are important for normal development, they enable cancer cells to grow rapidly, spread to distant sites, and evade therapy. With funding from ALSF, we discovered that HMGA1 genes are highly expressed in Burkitt’s lymphoma, an aggressive childhood cancer, as well as other types of childhood leukemia and lymphoma. More recently, in collaboration with the Children’s Oncology Group, we found that high levels ofHMGA1 correlate with relapse in B-lineage acute lymphoblastic leukemia, the most common form of childhood leukemia. We also discovered that HMGA1 transforms normal blood cells into leukemia cells, while blocking HMGA1 causes the cancer cells to revert back to cells with a normal growth pattern and appearance. We developed genetically engineered (transgenic) mice overexpressing HMGA1 and all mice develop aggressive leukemia that closely mimics childhood leukemia. We also discovered pathways that are turned on by HMGA1 in leukemia cells and could be blocked with novel therapy. Moreover, some of these novel therapies have been tested in our preclinical mouse models with promising results. Current efforts are directed at improving these treatments and discovering new approaches to block HMGA1 in therapy for children with leukemia or other cancers. Because HMGA1 is highly expressed in all aggressive childhood cancers, our work will have an impact on diverse cancers and should lead to improved therapies as well as novel markers to identify children at risk for more aggressive disease.