The National Cancer Institute (NCI) has renewed a longstanding Program Project Grant (PPG) that will enable a team of researchers at the College of Veterinary Medicine, OSUCCC – James, and Washington University Siteman CCC in St. Louis to continue studying retrovirus models of cancer.
The $9.1 million, five-year grant renewal, which extends through 2025, was awarded to principal investigator (PI) Patrick Green, PhD, associate director for basic research at the OSUCCC – James and director of the Center for Retrovirus Research in Ohio State’s College of Veterinary Medicine (CVM). Green is also a professor and associate dean for research and graduate studies in the CVM and holds the Robert H. Rainier Chair in Industrial Veterinary Medicine and Research.
The goal of this PPG, which has been operational at Ohio State since 2003 and is the longest-running PPG at the university, is to use a human T-cell leukemia virus type 1 (HTLV-1) T-cell immortalization model to gain an understanding of the microenvironmental, cellular and viral factors that lead to adult T-cell (ATL) leukemia. With this knowledge, the researchers hope to identify targets for diagnosis and treatment of HTLV-1 infection, ATL and related leukemias and lymphomas.
Co-investigators in the PPG include: Amanda Panfil, PhD, Stefan Niewiesk, DVM, PhD, and Krista La Perle, DVM, PhD, from the CVM; Kristine Yoder, PhD, Soledad Fernandez, and Lianbo Yu, PhD, from Ohio State’s College of Medicine; Amanda MacFarlane, PhD, from the OSUCCC; and Lee Ratner, MD, PhD, Katherine Weilbaecher, MD, and Deborah Veis, MD, PhD, from Washington University. Panfil, Niewiesk and La Perle are in the Leukemia Research Program at the OSUCCC – James, where Yoder is in the Molecular Carcinogenesis and Chemoprevention Program, and Fernandez is in the Cancer Biology Program.
Green says the PPG has three projects and three cores:
Project 1: Role of HTLV-1 HBZ in Transformation and Disease. (Leader: Patrick Green, PhD; Co-I: Amanda Panfil, PhD). This project will characterize the mechanism of HBZ gene products relating to HTLV-1 infection, viral latency and emergence of ATL. The major focus is on identifying and characterizing cellular binding partners that interact with HBZ messenger RNA (mRNA) and HBZ protein and to determine the impact of those interactions on viral pathogenesis.
Project 2: Effect of HTLV-1 Viral Oncogenes on the Bone Marrow Microenvironment in ATL. (Leader: Katherine Weilbaecher, MD; Co-I: Deborah Veis, MD, PhD). This project will define the molecular mechanisms that HTLV-1-transformed cells use to interact with cells in the bone microenvironment, which include osteoblasts, bone marrow stromal cells, macrophage lineage cells and osteoclasts. Researchers also will focus on the relationship between HTLV-1 HBZ gene expression and both the Wnt non-canonical pathway (involving Wnt5a) and the HPSE gene. This work will utilize mouse transgenic and humanized animal models to evaluate the relevance of these pathways on HTLV-1 bone pathology.
Project 3: Role of CTCF in HTLV-1 Replication and Transformation. (Leader: Lee Ratner, MD, PhD). Researchers will determine if and how the CTCF gene modulates the behavior of HTLV-1-infected T cells as it relates to virus expression, HBZ gene regulation, methylation of provirus elements, site of virus integration and effect on surrounding host genes.
Administrative and Biostatistics Core. (Director, Patrick Green, PhD; Co-I: Amanda MacFarlane, PhD, Soledad Fernandez, PhD, Lianbo Yu, PhD). This core carries out overall administrative functions and offers biostatistics support.
Virus Vector Core. (Director, Kristine Yoder, PhD). This is a new core to support the individual PPG projects in the design of custom viral vectors.
Animal Core (Director: Stefan Niewiesk, DVM, PhD; Co-I: Krista La Perle, DVM, PhD). This core will support the development and use of the rabbit model and various applications of the NSG™ (immunodeficient) mouse model within this PPG.
In their project abstract, the researchers state that in the previous funding period of this PPG, they advanced understanding of how retrovirus proteins contribute to cell immortalization, how retroviruses cause cellular changes that position infected cells to progress to metastatic cancer and how ATL cells contribute to paraneoplastic disease syndromes and can be targeted for anticancer therapy.