Project 458759

Acute myeloid leukemia is an aggressive form of blood cancer. Although remission after initial treatment is common, for many patients the disease returns, oftentimes in a more aggressive and treatment-resistant form. This high relapse-rate contributes to poor overall patient survival. I am focusing on understanding how the biology of leukemia cells responsible for driving relapse, called "leukemia stem cells" (LSCs), differs from normal blood stem cells, called "HSCs". The aim is to identify important targets for which novel LSC-targeted therapeutics may be developed to eliminate the leukemia while leaving the HSCs relatively unharmed. Towards this goal, the Hope lab used a novel approach to identify, from hundreds of candidate proteins, those that are specifically essential for LSC survival. Importantly, of those proteins identified to be critical for leukemia growth, nearly half are involved in a cellular formation which occurs in stressed cells, known as "stress granules" (SGs). SGs are clusters of closely associated RNA and protein molecules and have gained significant attention as they are implicated in cancer metastasis and treatment resistance. However, there remains a gap in the understanding of SGs in leukemia. Our findings suggest that LSCs depend on SGs for survival. To investigate this further I will use state-of-the-art microscopes to analyze when and how SGs form in leukemia cells compared to HSCs. I will further experimentally decrease or increase SG forming proteins in leukemia vs normal blood cells to determine how impairing SGs impacts leukemia maintenance. Finally, I will use a technique called BioID to look at the protein composition of SGs in LSCs vs HSCs to identify LSC-specific ones and to further manipulate these to determine their impact on leukemia survival. With this research, I aim to map SG dynamics in leukemia and to uncover SG proteins which may be targeted for the development of novel LSC targeted therapies.