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Understanding the Mechanisms of HOX Gene Regulation in Normal and Leukemic Hematopoietic Stem Cells to Identify New Therapies for Pediatric AML

Institution: 
Boston Children's Hospital
Researcher(s): 
Anne Robertson, PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2017
Type of Childhood Cancer: 
Acute Myelogenous Leukemia (AML)
Project Description: 

Background 

Acute myeloid leukemia (AML) is the second most common form of childhood leukemia. It arises due to mutations that affect blood stem cells, causing them to proliferate excessively and give rise to immature, leukemic cells. Current treatment involves chemotherapy and bone marrow transplantation, but these cells are difficult to eliminate and overall survival rates remain lower than 70%. It is essential that we identify new ways to treat pediatric AML, but this is challenging because we do not fully understand the mechanisms regulating proliferation in blood stem cells, or what makes them go into overdrive. Zebrafish can develop blood cancers in the same way as humans, making them a very powerful chemical and genetic screening tool. We have generated a zebrafish model overexpressing the same gene that is often overexpressed in pediatric AML, giving us a unique way to study the molecular mechanisms of this disease. Just like cancer patients, these fish don't develop mature white blood cells, giving us the opportunity to look for ways to rescue this phenotype. 

Project Goal:

My first goal is to identify compounds that can promote white blood cell development in this model, which may have therapeutic benefit in pediatric AML. My second goal is to decipher proliferation mechanisms by looking for gene regulators that promote either normal blood stem cell or leukemia cell expansion in zebrafish. This will identify pathways that malfunction in AML and could be targeted therapeutically without harming normal blood cells. It will also reveal new ways to expand HSCs for transplantation.