Grant: CIHR Fellowship

Leukemia is a type of cancer that affects blood and bone marrow. The protein ETV6 has been widely implicated in various forms of leukemia and is an important therapeutic target. ETV6 is a transcription factor that plays key roles in the formation of blood cells. Proteins, such as the ETV6 transcription factor, are biological "lego-blocks" that make up the molecular machines used to read the genes encoded within our DNA. Depending on the biological context, such as cell and tissue type, these proteins can associate with different partners (other lego-blocks) in the molecular machines and dictate when and which genes are read. Moreover, various cellular cues can result in chemical modifications, such as phosphorylation, of these proteins causing changes in their shapes and thus, altering their functions. ETV6 function is also tightly controlled by these mechanisms. However, it sometimes has the wrong structure because its DNA-binding lego-block is incorrectly joined to a completely different protein, thus creating a mutant transcription factor that causes leukemia. More than 40 such mutants have been reported. Excitingly, we have discovered that parts of ETV6 inhibit its own ability to read genes, thus regulating its function. We hypothesize that this autoinhibition is important for the proper functioning of ETV6 in normal cells, while lack of this regulatory mechanism can lead to cancer. ETV6 function is also regulated by phosphorylation and partnerships with other proteins. I am using the techniques of NMR spectroscopy and X-ray crystallography as "molecular microscopes" to study the molecular basis of the function and regulation of ETV6. This will enable us to understand the critical role of ETV6 autoinhibition and how it is disrupted in ETV6 mutants involved in cancer. Additionally, this research may provide a "molecular blueprint" for therapies to inhibit the deregulated function of ETV6 and thereby prevent it from causing cancer.