Early Career Investigator Award

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First Inaugural Early Career Investigator Grant Recipient

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Zuzana Tothova, MD, PhD

Investigator, Dana-Farber Cancer Institute, Instructor in Medicine at Harvard Medical School, Associate Member of the Broad Institute, and principal faculty in the Harvard Stem Cell Institute


Summary of Research Proposal
The RUNX1 gene encodes a protein that falls into a specific category of proteins called transcription factors. Transcription factors are proteins that can control the output of protein production from other genes. Transcription factors are analogous to a hand turning a light switch on or off, where the switch represents the control of many genes. RUNX1 is a critical transcription factor for blood cells. Yet RUNX1 cannot exert its function of turning on or off different genes in the blood without its specific protein partners. When RUNX1 and its partners form a complex, only then will the on or off switch controlling other genes work.

In diseases, like RUNX1-FPD where a transcription factor is not working at 100% capacity or is in some way dysfunctional, some blood cells attempt to adapt and compensate for the deficiency and this adaptation can lead to cancer. Dr. Tothova and colleagues have found that in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), cells with mutations in RUNX1 often also have mutations in a gene called STAG2. This second mutation in STAG2 is evidence of an adaptation made by the cells. STAG2 is a protein involved in gene activation because of its key role in controlling the architecture of DNA. Dr. Tothova’s research is focused on understanding why mutations in STAG2 help diseased blood cells survive and expand. She is doing this by evaluating liquid-liquid phase separation condensates in healthy blood cells versus RUNX1-FPD blood cells. Liquid-liquid phase separation was only very recently described as a new model of gene control. This model suggests that the areas in which gene control is occurring, within the core of the cell (the nucleus), are physically distinct and form structures like water droplets in order to compartmentalize these critical cellular reactions. Dr. Tothova hypothesizes that the liquid phase condensates, the water droplets, in RUNX1-FPD blood cells are reorganized. Her research aims to uncover a new therapeutic strategy that would specifically target mutant phase condensates in RUNX1-FPD blood cells that are transforming into cancer cells, potentially stopping cancer formation in its tracks.