Disrupting the Proteostasis Network in Acute Myeloid Leukemia

About This Grant

PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common form of adult acute leukemia yet has a 5-year overall survival of only 32.9%. Thus, identifying new strategies to target AML would address a critical unmet need for patients. Protein homeostasis (proteostasis) refers to a network of mechanisms used to maintain the quality of the proteome. The role of proteostasis regulation in AML has not yet been thoroughly examined. Proteasome inhibitors are approved to treat multiple myeloma, but they exhibit little clinical efficacy in AML. They work well in myeloma because they readily disrupt proteostasis in myeloma cells which already exhibit increased basal levels of proteotoxic stress from paraprotein production, resulting in activation of an integrated stress response (ISR). The ISR is a stress pathway activated by eIF2a and can ultimately induce apoptosis. In contrast to myeloma, AML cells require additional perturbations to the proteostasis network to activate the ISR when treated with proteasome inhibitors. I recently found that proteasome inhibition induces compensatory activation of the autophagy and the heat shock response pathways to preserve proteostasis. However, disruption of either autophagy or the heat shock response in combination with proteasome inhibition potently kills AML cells by activating a terminal ISR. This raises the possibility that the integrated nature of the proteostasis network confers resistance to proteasome inhibition, and that concurrent targeting of multiple mechanisms is required to disrupt proteostasis. The central goal of this proposal is to test the hypothesis that disrupting the proteostasis network can impair AML. In Aim 1, I will disrupt proteostasis within AML cells by inhibiting protein degradation with both proteasome and autophagy inhibitors, and determine if PKR, an eIF2a kinase, mediates ISR activation during this process. I will also determine if proteostasis disruption increases IL24, an immunomodulatory cytokine, and perform proteomics studies to determine whether it can be used as a biomarker for proteostasis disruption. In Aim 2, I will examine if proteostasis disruption through deletion of HSF1, a master transcription factor of the heat shock response, coupled with proteasome inhibition activates PERK, another eIF2a kinase, to turn on the ISR. This project will utilize vertebrate animals for establishing humanized cancer models to evaluate the in vivo effects of modulating proteostasis which would be a necessary step toward translational studies. Overall, I will begin to uncover how the proteostasis network is configured within AML in vitro and in vivo, and establish how it can be therapeutically targeted. My career goal is to become a physician-scientist who will make discoveries leading to new therapies for patients with hematologic malignancies. For this K08 award, I have assembled an exceptional team of experts at UC San Diego, a world-renowned research institution, that will provide training on the proteostasis network, state-of-the-art proteomics, and translational research in AML. With outstanding institutional support and an accomplished mentoring team, I aim to gain additional skills necessary for leading a successful laboratory in translational research and develop proteostasis-targeting therapies in blood cancers.