Project 458583

Leukemias originate from the accumulation of mutations within hematopoietic stem cells, which are responsible for replenishing blood and immune cells for the body. Mild, pre-leukemic mutations in these cells often arise in healthy individuals by chance, but usually do not cause disease because the affected stem cell is kept under control and retains its normal functions. Instead, progression to disease only occurs once these pre-leukemic cells are able to replicate themselves and take over a significant portion of the bone marrow. Our research studies pre-leukemic mutations in the SRSF2 gene, which are particularly aggressive and highly associated with disease. However, these mutations are unique in that they seem highly constrained by the environment. Our work proposes that mesenchymal stromal cells (MSCs), a population of supportive cells in the bone marrow, are responsible for controlling the outgrowth of SRSF2 mutants. Conversely, dysfunctional MSCs can unleash or even cooperate with these mutants, allowing them to rapidly outgrow healthy hematopoietic stem cells and take the first steps towards leukemia. By analyzing cellular changes in MSCs in aged individuals or individuals with leukemias, we hope to identify the key factors that allow them to support SRSF2 mutant stem cells. We will evaluate whether these factors can be used to predict which individuals are at risk of leukemia. We will also assess whether targeting these pathways via drugs can restore the function of MSCs and re-establish control over SRSF2 mutants before they can propagate, or even reverse the progress of SRSF2 mutants that are advancing towards leukemia. We hope that our findings will contribute to the ability to prevent leukemias before they develop.