Inherited resilience to clonal hematopoiesis and myeloid malignancy by modifying stem cell RNA regulation

Genetic variation within the human population (1 in every 1,000 DNA letters) means that some individuals are more predisposed to acquire certain diseases than others. Conversely, some of this variation also protects certain people from disease. Genetic studies have shown that some individuals are more protected from getting blood cancer than others; however, the mechanisms remain largely undefined. Our research has identified a single genetic variant that significantly protects individuals from blood cancers. We have shown that the variant acts to reduce the activity of a key gene called MSI2 in blood stem cells, from which these cancers arise. Our proposed research seeks to understand mechanisms of how this genetic variant down tunes MSI2 levels, and how this impacts blood stem cells to enable natural blood cancer resilience. Our studies will identify how MSI2 controls the activity of other genes, to map out a broader network that is modulated through genetic variation to protect blood stem cells from cancer. The long-term goal of this research is to leverage these natural mechanisms to develop new treatment or preventive strategies. There are precedents for this approach: understanding genetic resilience has led to important therapeutic advances in cardiovascular disease prevention and a curative therapy for sickle cell anemia. If we confirm that lowering MSI2 levels protects against blood cancers without causing harmful side effects, it could pave the way for new drug treatments that mimic this natural protection. In the future, genome editing might even allow us to precisely regulate MSI2 activity in blood stem cells to prevent high-risk individuals from developing blood cancers.