The Role of TP53 in Mutant U2AF1 Myelodysplastic Syndromes

The goal of this project is to develop new ways to treat blood cancer patients who have mutations in RNA splicing genes. These splicing factor genes stitch together RNA, which is the genetic handbook that tells a cell how to grow. These mutations occur in half of patients with myelodysplastic syndrome (MDS), an aggressive blood cancer that affects over 60,000 Americans. Only 4 out of 10 patients with MDS will be alive 5 years after their diagnosis. As such, new treatment options are urgently needed. 

Our understanding of how splicing factor gene mutations cause MDS is incomplete. Our lab’s observations of blood cells with splicing factor gene mutation suggest they have a two-stage growth pattern. Early on, mutant cells grow poorly and struggle to keep pace with healthy cells. Later, the mutant cells adapt and ramp up their growth to outcompete and overwhelm healthy cells. The mechanisms that cause the transition from healthy to poor growth—and later from poor to rapid growth—remain unknown. We suspect a four-step process. First, splicing factor gene mutations cause a particular type of RNA structure to accumulate, called a R-loop. Second, these R-loops activate TP53—the primary regulator of cell growth. Third, high TP53 activity causes poor cell growth. And four, mutant cells increase their growth by finding  ways to inhibit TP53 . In this project, we will test key events along this four-step process. Understanding how mutated cells adapt to become cancer could lead to treatments to reverse this process and kill blood cancer cells in patients. 

For part 1 of this project, we will use mouse models of MDS and test if expressing RnaseH1 (which resolves R-loops), or MDM4 (which inhibits TP53) causes mutated cells to grow better. In part 2, we will test if drugs that inhibit RnaseH1 or MDM4 will preferentially kill splicing factor mutant blood cells. These experiments may tell us how blood cells with splicing factor gene mutations adapt to grow and cause MDS (part 1). Also, they may suggest that for MDS cells to stay alive, they rely on RnaseH1 to resolve R-loops and MDM4 to limit TP53 activity (part 2). 

Collectively, this project will provide key insights into how splicing factor mutant genes contribute to the onset of MDS. They may also suggest splicing factor mutant blood cells can be killed by drugs that inhibit RnaseH1 and/or reactivate TP53. We anticipate our studies to lead directly to new clinical trials that will assess these ideas in MDS patients.