Childhood Cancer

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Targeting HMGA1 in Pediatric T-cell Acute Lymphoblastic Leukemia

The Johns Hopkins University School of Medicine
Joelle Hillion, PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Leukemia, Acute Lymphoblastic Leukemia (ALL)
Project Description: 

Leukemia is the most common childhood cancer worldwide with almost 4,000 cases each year in the United States alone. Acute lymphoblastic leukemia (ALL) is cancer of the white blood cells and T-cell leukemia is a particularly aggressive subtype of leukemia that involves T-cells or white cells that develop in the thymus. T-cell ALL constitutes about 13-15% of all cases of childhood ALL.

Although treatment of childhood acute lymphoblastic leukemia has improved dramatically over the past 20 years, children with T-cell ALL remain at high risk for relapse and poor outcomes. Why T-cell ALL is resistant to therapy is still not known. Thus, research is urgently needed to discover how T-cell ALL develops so that children with T-cell ALL can be treated more effectively.

Our laboratory is studying genes that contribute to the development of childhood T-cell ALL with the longterm objective of designing better therapies. Our focus is the HMGA1a gene, which is overexpressed in cancer and correlates with a poor outcome in some tumors. The Resar laboratory discovered that HMGA1a is also overexpressed in T-cell ALL. They also demonstrated that HMGA1 causes normal white blood cells to grow like leukemia cells. Blocking HMGA1 function in leukemia cells causes the cancer cells to grow like normal cells, indicating that HMGA1 is responsible for the abnormal growth of these leukemia cells.

More recently, the Resar laboratory developed genetically engineered (transgenic) mice overexpressing HMG-I and all mice develop aggressive T-cell ALL, which closely models T-cell ALL in children. These studies demonstrate that HMGA1 functions as a cancer-causing gene (oncogene) important in T-cell ALL.

Project Goal
How HMGA1 causes normal T cells to transform into leukemic T cells is unknown. Thus, our overall goal is to elucidate the mechanisms involved in this process using our transgenic mice and other unique reagents. In preliminary studies, we discovered that HMGA1 activates the COX-2 gene in leukemogenesis. Importantly, drugs are available for use in humans that could block this gene and potentially kill leukemia cells. We also found that loss of function of the INK4A/ARF genes greatly accelerates leukemia in the HMGA1 mice. Interestingly, in childhood T-cell ALL, the INK4A/ARF genes are frequently lost by a form of mutation called deletions.

Our results indicate that loss of function of the INK4A/ARF genes cooperates with HMGA1 in inducing T-cell ALL. Now, we propose to further elucidate the role of HMG-I in T-cell ALL using our unique reagents, including our mouse models, cultured cell lines, and primary pediatric ALL samples. Our Specific Aims include:

1.) Determine if HMGA1 is a marker for more aggressive disease in T-cell ALL.

2.) Identify other genes that cooperate with HMGA1 in the development of T-cell ALL.

Results from our studies will advance our knowledge or T-cell ALL and should ultimately enable us to develop better therapies.