Date of Award

Spring 2022

Document Type

Open Access Dissertation

Department

Biomedical Engineering

First Advisor

Katie Kathrein

Abstract

We recently identified the tumor suppressor, Ing4, as a critical regulator of hematopoietic stem cell (HSC) homeostasis. The mis-regulation of Ing4 in human cancers has also been shown to lend malignant cells specific advantages that support carcinogenesis and tumor progression. This activity is, in part, due to Ing4 mediated regulation of overlapping signaling pathways that regulate stem cell activity and cancer cells, including NF-B and c-Myc. In a two-part study, we have investigated the role of Ing4 in murine hematopoiesis and human malignancies. While the specific mechanisms of stem cell self-renewal, maintenance, and differentiation are poorly characterized, we have determined that Ing4 deficiency induces G0 arrest in HSCs, while simultaneously promoting gene expression signatures associated with differentiation. We combined a biological and mathematical approach to constructing a multi-step model of hematopoiesis that provides new avenues to better understanding the role of Ing4 in hematopoiesis. Finally, a screen of small molecule NF-kB pathway inhibitors using in vitro and in vivo assays as well as a zebrafish xenograft model, demonstrated that the suppression of NF-kB through inhibition of various pathways may remediate the consequences of Ing4 loss in human cancers, opening potential avenues for novel cancer therapies that uniquely target malignant cells. Our combined models provide key tools to elucidate the crucial role that Ing4 plays in both hematopoiesis and cancer.

Available for download on Friday, May 31, 2024

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