Targeting HMGA1 in Childhood ALL

Although treatment of childhood leukemia has improved dramatically over the past 20 years, ~15% of children will ultimately relapse with poor outcomes.  Thus, research is urgently needed to discover how refractory leukemia develops in order to design better therapies.  Our laboratory is studying genes that cause childhood leukemia with the long-term objective of designing better treatments.  Our focus is the HMGA1 gene, which is overexpressed in many different types of childhood leukemia.  Moreover, high levels of HMGA1 correlate with poor outcomes in childhood leukemia.  HMGA1 also causes normal white blood cells to transform into leukemia cells.  Conversely, blocking HMGA1 function in leukemia cells causes the cancer cells to grow like normal cells.  Using our unique experimental models, we have begun to identify other genes that cooperate with HMGA1 to cause leukemia and we are studying agents that block these pathways and could be adapted for use in therapy.  In addition, we have begun to identify small molecules, called microRNAs, that are repressed by HMGA1 in leukemia.  Some of these microRNAs appear to function as tumor suppressors or molecules that block or "suppress" tumor growth.  We have developed a novel strategy to replace microRNAs.  Here, we propose to use our innovative reagents to treat leukemia in preclinical models with microRNA replacement therapy and other small molecules.  Our proposed studies will provide a paradigm for the novel treatment of leukemia with microRNA replacement therapy.  If successful, these studies could be translated to the clinic to improve outcomes for children with refactory leukemia. 

Project Update

Amy Belton spoke to us about her research (October 2013):

What were you initially studying with your grant funded by ALSF?
My goals for this project were to uncover new pathways that cause childhood leukemia and to develop novel approaches to target these pathways. Our focus has been on an exciting group of proteins, called chromatin remodeling proteins, which help the cells in our body to function normally. They are involved in regulating how cells grow and divide, particularly during embryonic development. The protein that I study, called the high mobility group A1 protein (or HMGA1), appears to play a fundamental role in diverse childhood cancers. In fact, this protein is highly expressed in all aggressive cancers studied to date. I have been using innovative animal and cell models in the laboratory to better understand how HMGA1 promotes cancer growth.       

What have you found?
I found that normal stem cell pathways are activated during the development of leukemia in our experimental models of childhood leukemia, and this work was published in BMC Genomics in 2012. These results tell us that leukemia cells “hijack” pathways used by normal stem cells when they become cancer cells. Our work also demonstrates that stem cell pathways help the cancer cells to grow and evade therapy. More recently, I have been testing small molecule inhibitors to target stem cell pathways and my preliminary results have been very promising. One such pathway involves HMGA1 and a protein called STAT3. I found that blocking STAT3 helps to prevent tumor growth in leukemia cells. Part of this work was published this year in the journal Leukemia and Lymphoma. I also have ongoing studies to look at an inhibitor that we believe to be more effective. In addition, I contributed to a study demonstrating that HMGA1 is a marker for relapse in pre-B acute lymphoblastic leukemia, the most common form of childhood leukemia.  (This work was also published in Leukemia and Lymphoma this year). I am also exploring additional pathways that could be targeted in childhood leukemia. 

What does this mean for children with cancer and their families?
These studies have helped to identify pathways that could be targeted to treat children with leukemia and have provided groundwork necessary to translate these approaches to the clinic. We believe that our work brings us closer to finding cures for all childhood with leukemia. Some of the pathways that we are studying will also be relevant to other tumors that affect children.

What are your next steps?
My next steps will be to further assess the efficacy of the inhibitors in our models of childhood cancer. In addition, I continue to search for additional pathways that could be targeted in childhood leukemia. 

Has this research been published?
My research funded by Alex Lemonade Stand Foundation has resulted in 5 papers directly related to childhood cancer.  I also have an ongoing study with a novel STAT3 inhibitor that will be completed shortly and submitted for publication. In addition, I am beginning to explore another pathway in childhood leukemia that involves HMGA1 and a protein complex called NF-κB. My preliminary results suggest that this pathway also plays an important role in the development of childhood leukemia. This is particularly exciting because there are inhibitors to NF-κB that could be used in therapy for children with leukemia.    

What has this grant from ALSF allowed you to do that you wouldn’t be able to do so otherwise?
The grant from ALSF has been instrumental in providing the funding necessary for me to study childhood leukemia. This support is particularly important due to funding cuts from other agencies for cancer research, particularly for cancer research that involves children. Our long-term goal is to identify inhibitors that could lead to improved survival for children with cancer. 

Why did you choose to work in this field/on this topic?
Childhood cancer is devastating and causes needless suffering. I work in this area so that I can apply my skills and expertise to fight childhood cancer and help to find cures for childhood leukemia.  

How did you benefit from being mentored during this project; what was most helpful?
My mentorship during this project has been very helpful. Since my postdoctoral fellowship, Linda has served as both a supportive and thoughtful mentor. I appreciate her support and tremendous contribution to my projects and I look forward to working with her in future.

From Dr. Belton's mentor, Linda Resar, MD, Associate Professor, The Johns Hopkins University School of Medicine, regarding mentoring her:
I have been privileged to mentor Amy in her research on childhood leukemia, which would not have been possible without the generous support of Alex’s Lemonade Stand Foundation. Amy is a bright and creative scientist, and her energy and dedication have been instrumental in the many discoveries summarized above. Her work has uncovered novel pathways involved in childhood leukemia and we are now working on approaches to target these pathways to improve outcomes for children with cancer.