This competitive renewal application (P01CA100730) seeks funds to continue our highly integrated studies of retrovirus models to elucidate cellular mechanisms of lymphocyte transformation and associated lymphoproliferative disease. Infection of CD4+ T-cells with the human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), induces their immortalization and enables those cells to accumulate genetic mutations leading to the malignant cancer, adult T-cell leukemia (ATL). The advantage of the HTLV-1 model to study leukemogenesis is the rapid induction of T-cell immortalization brought about by the viral infection. This model of leukemogenesis allows careful examination of the biologic changes and response patterns of virus infected preneoplastic cells while under the influence of cellular and viral factors that control and perhaps promote progression to cancer. In the previous funding period, we made substantial advances in our understanding of: 1) how retrovirus accessory proteins contribute to cell immortalization; 2) how retroviruses cause broad cellular changes that position infected cells to progress to a metastatic cancer; 3) and how ATL cells contribute to paraneoplastic disease syndromes, and can be targeted for anticancer therapy. In the next funding period, the overall theme of the Program Project is to continue our studies with HTLV-1 leukemia model with a focus on discovering how key viral, cellular and microenvironmental factors work in concert to promote T-cell cancer. We now recognize three interrelated areas of study that are major gaps in our understanding of the pathogenesis of HTLV-1-associated T-cell leukemogenesis: 1) Mechanism of action of HTLV-1 multifunctional hbz mRNA and HBZ protein; 2) The effect of HTLV-1 CTCF-BS (11-zinc finger CCCTC factor-binding site) on T-cell immortalization, hbz expression, establishment of latency and contribution to the transition to ATL, and; 3) Microenvironmental factors that contribute to the survival and expansion of HTLV-1-infected T-cells and their progression to ATL.

Public Health Relevance

The ultimate goal of this P01 Program Project Grant (PPG) competitive renewal application is to utilize the HTLV-1 T-cell immortalization model to gain understanding of the microenvironmental, cellular and viral factors that lead to progression to leukemia, and with this knowledge, to identify unique targets for diagnosis and treatment of HTLV-1 infection and ATL and related leukemia/lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA100730-16A1
Application #
10023350
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2003-04-21
Project End
2025-05-31
Budget Start
2020-09-01
Budget End
2021-05-31
Support Year
16
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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