Advisors:

Dr. Shuichi Takayama (Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University)

Dr. Douglas K. Graham (Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine) 

Committee:

Dr. Mark Styczynski (School of Chemical and Biomolecular Engineering, Georgia Institute of Technology)

Dr. Melissa Kemp (Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University)

Dr. Sunil Raikar (Department of Pediatrics, Emory University School of Medicine)

Developing High Throughput and Long-Term Human Bone Marrow Perivascular Organoids for Modeling Acute Myeloid Leukemia 

The human bone marrow (BM) microenvironment is a complex system composed of hematopoietic progenitor cells (HSPC) and a non-hematopoietic stroma formed by endothelial and mesenchymal stem cells (MSC). This 3D structure regulates blood cell production through specialized niches. Replicating this complexity, especially for acute myeloid leukemia (AML), is challenging. AML, a blood cancer with a poor prognosis, is further complicated by the BM tumor microenvironment (TME), which creates a protective environment that limits therapy efficacy. Current in vivo models are limited by reliance on animal physiology, high costs, and low throughput, while in vitro models often lack the spatial and cellular complexity of the BM microenvironment and have a short lifespan. To address these limitations, herein the development a human in vitro vascular BM model that accurately recapitulates the 3D AML BM TME is proposed. This model will support long-term AML cell proliferation and enable high-throughput screening of therapeutic agents. Aim 1 involves establishing BM stroma organoids by co-culturing MSCs and HUVECs in various ratios, with structural and functional characteristics analyzed through imaging, immunofluorescence, and single-cell RNA sequencing. Aim 2 focuses on creating AML BM organoids by co-seeding AML cells with MSCs and HUVECs, optimizing organoid formation, and assessing their architecture, cell composition, and TME features. Aim 3 evaluates the protective effect of the AML TME on Ara-C and MRX-2843 drug therapies through drug response assays.