Modeling GATA2 Associated MDS/AML Predisposition Syndrome Using Color-Barcoding and Mutagenesis in Zebrafish
Children and young adults with inherited mutations in the GATA2 gene have an increased risk of developing blood cancers. These cancers arise from abnormal blood stem cells. The mutant stem cell clone multiplies and expands, acquiring additional mutations that promote leukemia formation. The process is poorly understood, especially in the context of predisposition syndromes to myeloid cancers.
To study the steps leading to cancer formation, I generated a zebrafish model with gata2 mutation. My goal is to understand the biology of gata2 mutant stem cells during development and in young adulthood at a level of individual blood stem cells. I use a special technique of coloring blood stem cell clones, which results in groups of colored blood cells, each representing the progeny originating from a same-colored stem cell clone. In normal hematopoiesis the contribution from stem cells is balanced, resulting in multicolored blood production. However, in the presence of gata2 mutation and additional acquired mutations, a precancerous mutant clone expands and a dominant color emerges. I will test the role of specific mutations in gata2 mutant zebrafish in their ability to promote clonal dominance and eventually leukemia. I will also focus on understanding the effect of gata2 mutations on stem cells during development in zebrafish embryos, as this may be the key to explaining the risk of cancer later in life. Zebrafish is an excellent model organism for studying blood diseases, and presents a unique system to perform chemical screens with a goal of finding new therapeutic modalities for myeloid cancers.