Proteostasis regulators in blood cell development and function

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The goal of research in my lab is to better understand the process of blood cell generation from hematopoietic stem cells (HSC) in the bone marrow as well as the differentiation of committed blood cell lineages and to apply this knowledge to elucidate the mechanisms of blood cell dysfunction and malignancy. While it is widely appreciated that genome integrity is required for normal development of mammalian cells including blood cells, a major gap exist in our knowledge of whether and how maintenance of proteome integrity shapes blood cell development, fate and function. Notably, not only does the proteome comprise the largest macromolecular content in cells, dynamic changes in proteome abundance, quality and protein modifications accompany the differentiation required for blood cell generation and protective immunity. Thus, blood cells must continuously navigate significant proteome stress and perturbations to proteome homeostasis (or "proteostasis") to successfully complete their differentiation and execute their function. Our research uniquely explores how defects in proteostasis regulators and their signaling pathways contribute to immune cell dysfunction and the emergence of blood cancers. We specifically use state-of-the-art transcriptomics, genomics, and proteomics to dissect how key mediators of the unfolded protein response (UPR) and modulators of the ubiquitin proteasome system (UPS) impact normal and malignant blood cell development and function in animal models and relevant human cell systems. So far, we have uncovered novel mechanisms of hematopoiesis and blood cancer pathogenesis. Recently, we uncovered that the IRE1 signaling branch of the UPR protects HSPCs from acute myeloid leukemia (AML) and that activation of this pathway can mitigate AML cell propagation. We also discovered that CHMP5, a novel UPS-modulating factor, is critically required for thymocyte malignant transformation such that loss of CHMP5 impairs T-cell acute lymphoblastic leukemia (T-ALL) initiation and maintenance. On-going research in the lab are aimed at the following goals: investigate the basis of our novel discovery that UPR deficiency is a significant driver of T cell exhaustion that limits protective immunity to chronic virus infections and cancers; define how proteostasis sensing promotes apoptosis that maintains the quality of the bone marrow HSC pool; examining how failure in proteostasis can result in chronic inflammation in tissues like muscles. Our long-term goal in these studies is to generate fundamental knowledge on the role of proteostasis in blood and immune cell biology and to harness our understanding of these proteostasis pathways in the design of novel and potent therapies against blood cell diseases.