The role of MRP1 in regulating oxidative stress-induced hematopoietic stem cell (HSC) and leukemic stem cell (LSC)

BACKGROUND: Acute myeloid leukemia (AML) is a significant problem in the United States. One hallmark of AML is a high level of reactive oxygen species (ROS), which results in increased oxidative stress. In leukemia stem cells (LSCs), the role of oxidative stress and the impact of increased oxidative stress are unclear. Our preliminary studies strongly suggest that MRP1 plays a role in regulating normal hematopoietic stem cell oxidative stress levels, self-renewal, and growth. Therefore, we ask if MRP1 has a similar role in regulating LSC self-renewal, growth, and disease progression HYPOTHESIS: We hypothesize that downregulation of MRP1 in AML decreases cellular oxidative stress via decreased GSH efflux, and results in increased LSC self-renewal, decreased differentiation and slowed disease progression. SPECIFIC AIMS: Specific Aim 1: Determine if reduced MRP1-mediated regulation of LSC oxidative stress via GSH efflux plays a role in the growth of acute myeloid leukemia (AML) using an AML mouse model. Specific Aim 2: Verify that down-regulation of MRP1 in AML results in increased cellular GSH, decreased oxidative stress and decreased expression of oxidative stress response genes in patient samples STUDY DESIGN: In Specific Aim 1, we will generate an AML mouse model and transplant MRP1 expressing and nonexpressing LSCs and monitor leukemia growth. In Specific Aim2 we will collect patient AML samples and correlate MRP1 and oxidative stress response genes expression to leukemia progression. CANCER RELEVANCE: Results from this study will have a direct impact on treatment of patients and overall survival.