St. Jude Children's Research Hospital
Project Term: July 1, 2023 - June 30, 2026
GATA2 deficiency is an inherited pediatric syndrome with a high rate of progression to myeloid malignancy, the mechanisms of which remain largely undefined. Here, we will use our recently generated mouse model, Gata2R396Q, to determine the effects of GATA2 deficiency on hematopoietic function and identify novel drivers of myeloid malignancy via focused CRISPR screens. Our work will provide further insight into the mechanisms driving leukemic progression of this syndrome.
GATA2 deficiency is a rare, inherited genetic syndrome found in children that arises from mutations in GATA2, which is a gene that is critical for proper blood development. These mutations result in a non-functional protein, which can lead to immunodeficiency, lung disease, vascular/lymphatic defects, and myelodysplastic syndrome (MDS). MDS is a disorder in which the bone marrow does not produce enough healthy blood cells and can often progress to acute leukemia. Of note, 75% of patients with GATA2 deficiency develop some form of blood disorder by early adulthood. Mutations in GATA2 alone are unlikely to cause the development of MDS, and while previous research has shown that patients with GATA2 deficiency who progress to MDS also have mutations in other genes and whole or partial loss of chromosome 7, the exact reasons why people with this syndrome are at higher risk for blood disorders are still unknown. To better understand this, we have created a mouse model with a common GATA2 mutation, Gata2R396Q. These mice express a mutated form of GATA2 in every cell of their body, including blood cells. Given the importance of GATA2 in blood development, we first aim to determine the effects of Gata2R396Q on normal blood function and development. We will do this by isolating blood cells from mutant mice and quantifying the presence of specific cell types, as well as testing the function of these cells compared to normal blood. We expect that this will give us insights into how the GATA2 deficiency affects blood development in humans, predisposing them to MDS and leukemia. Next, given the recurrence of chromosome 7 loss in disease progression, we aim to identify the specific genes on this chromosome whose loss that drive malignancy. To do this, we will use a screening approach to test the effect of deleting different genes on chromosome 7 in our Gata2R396Q mice to see which deletion(s) result in leukemic progression. Through our studies, we will gain valuable insights into the mechanisms of leukemia progression in GATA2 deficiency which will facilitate development of novel therapies to prevent or treat the related malignancies.