PROJECT SUMMARY

Myelodysplastic syndrome (MDS) is a disease that keeps the body from properly producing enough healthy blood cells. The disease is more common in older patients, but also occurs in children and young adults. MDS can manifest as a low-grade disease that remains stable for years, but in many cases, the disease progresses to aggressive leukemia that is difficult to cure.

Over the last few years, increasing evidence indicates that MDS can result from an inherited predisposition. This is particularly true for children and younger adults with MDS. GATA2 is an important gene required for normal blood cell formation. A broken (mutated) GATA2 gene causes MDS and other organ dysfunction. MDS patients with GATA2 mutations can be stable for years or rapidly progress to aggressive leukemia. The reasons for this wide spectrum of disease manifestation are unresolved. Uncovering the mechanisms that trigger low-grade or high-grade disease will likely lead to more effective treatments and strategies to predict which patients are at higher risk for leukemia. To date, no effective medications to treat GATA2-related MDS exists, and bone marrow transplantation remains the only curative therapy. Importantly, not all patients are eligible for transplant therapy, and transplant therapy is not always successful.

GATA2 function requires multiple other factors that operate like an orchestra where all instruments must be finely tuned and integrated with each other. In this study, a team involving a laboratory scientist and clinical scientist that treats children with MDS and leukemia, will combine efforts to better understand how GATA2-regulated genes that form “networks” work and how they cause MDS and leukemia in children and young adults. We aim to discover prognostic markers and targets for new therapies to improve the outcomes of children with MDS and leukemia that are currently only cured with bone marrow transplantation.

Over the past 2 years, we have isolated and stored bone marrow samples from children and young adults with MDS due to GATA2 mutation to analyze how mutations derail GATA2 function in comparison to its normal activity in healthy people. This first test revealed that patients with GATA2 mutations have different “networks” in their blood cells compared to normal. Using this method, we could distinguish normal individuals from diseased patients. Remarkably, the molecular signatures of the gene networks allowed us to distinguish patients with low-grade MDS from those with high-grade MDS. While we did not have sufficient patient samples to draw conclusions we were able to lay a foundation for more in depth single cell analysis in the future. Furthermore we developed mouse model systems to elucidate consequences of GATA2 mutations occurring in patients. These model systems are providing powerful tools to further understand the biology of GATA2 mediated MDS and offer a screening system for future therapeutic interventions.