$9.1 million NCI grant renewal will support researchers studying retrovirus cancer models

The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) and The Ohio State University College of Veterinary Medicine (CVM) have been awarded a five-year, $9.1 million grant Program Project Grant (PPG) renewal from the National Cancer Institute (NCI).

The PPG grant has been continually funded since 2003 and will allow investigators from the OSUCCC - James, CVM and collaborators at the Washington University - St. Louis Siteman Cancer Center to continue studying retrovirus models of cancer.

The grant renewal extends through 2025 and is led by principal investigator Patrick Green, PhD, associate director for basic research at the OSUCCC - James and director of the Center for Retrovirus Research at the CVM.

The goal of this PPG 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.

"This is a powerful area of basic research we expect to result in new targets for the treatment of HTLV-1 infection, ATL, and related leukemias and lymphomas," says Green, who also serves as 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.

This grant has allowed our multidisciplinary team to advance 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. These are important discoveries, and this renewed funding with allow us to continue momentum in this area of cancer research."

Patrick Green, PhD, Principal Investigator

The collaborative research grant is organized around three research projects and three research cores.

Projects include:

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.

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.

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.

The PPG also supports administrative/biostatistics, virus vector and animal research cores relating to this ongoing retrovirus research.

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 - James; 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.