Identification of FDA-approved Drugs that are Selectively Active Against Hematopoietic Stem and Progenitor Cells with Inactivating Mutations of TET2

Background

TET2 is one of the most frequently mutated genes across the spectrum of myeloid malignancies. Recent findings have demonstrated that mutations in TET2 are considered to be the "first-event" in hematopoietic stem cells (HSC) in individuals who develop myeloid malignancies. The acquisition of TET2 mutations leads to clonal expansion of the abnormal stem cell, which then accumulates mutations in other genes, leading to the onset of myeloid malignancy. The goal of our study is to find small-molecules that will kill the blood stem cells harboring TET2 mutations, but not the healthy normal stem cells, thus preventing the clones that lack the TET2 protein from expanding further and acquiring additional defects in other genes.

Project Goal

For my study, I will use a TET2 mutant zebrafish model that lacks TET2 protein and develops clonal myelodysplasia. This model is ideal because it has not fully developed cancer, but the clonal expansion of HSCs that lack the TET2 protein has already occurred. We will use these zebrafish mutant embryos to perform a drug screen with known drugs, including those that are already approved by the FDA. This strategy, called repurposing of existing drugs, will accelerate the entrance of such compounds into clinical trials because the analysis of toxicity, side effects and other characteristics of these drugs have been already investigated. This project is significant because it will identify drugs that are able to specifically eliminate HSC that are predisposed to develop myeloid malignancies as the result of the TET2 gene inactivation.